Human Memory T Cell Formation
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The acquisition of antigen experience is marked by thegeneration and the persistence of memory T cells, whichcan provide life-long protection against pathogens.Studies of mouse models have shown the robust genera-tion of memory T cells that occurs in response to diversepathogens, and the efficacious protective responsesof these cells following reinfection; however, the role ofmemory T cells in protecting and maintaining long-termhealth in humans is less clear.
In mouse models, it is well-documented that antigen-specific naive CD4+or CD8+T cells become activatedfollowing antigen exposure, and that populations ofthese cells subsequently undergo proliferative expansionand differentiation into effector T cells. It is generallythought that these activated, effector T cell populationscontain the precursors of antigen-specific long-livedmemory T cells, which persist in vivoas heterogeneouspopulations in multiple sites, and can coordinate protec-
tive immune responses following pathogen re-exposu re.Mouse memory CD8+T cell-mediated protection hasbeen shown in the well-characterized lymphocyticchoriomeningitis virus (LCMV) infection model andfor additional mouse pathogens (reviewed in REFS 1,2).In mice, memory CD4+T cells can similarly mediateprotective immune responses to influenza virus35,Mycobacterium tuberculosis6and parasite7infections.
Although most of our current understanding ofmemory T cell generation, function and maintenanceis based on results from mouse models, studies in micecannot recapitulate the exposure to multiple pathogensthat occurs in humans over decades. The duration of a
mouse memory study is typically several months (thelifespan of laboratory mice can be 23 years), whichconstitutes only a small fraction of the duration ofimmunological memory that occurs over many decadesin humans (who have an average lifespan of 75 years).In addition, humans are exposed to diverse pathogensthrough the aerodigestive tract, genital mucosa and skin,which are sites of extensive colonization by >2,000 spe-cies of commensal microorganisms8. By contrast, mostexperimental mice are maintained in highly stringent,pathogen-free conditions that limits the breadth of theircommensal diversity. Therefore, the generation and themaintenance of human memory T cells should be con-sidered in the context of the unique human exposure topathogenic and non-pathogenic microorganisms, andnot only relative to mouse models in controlled in vivosettings.
Human T cell studies are generally limited in two
respects: first, most studies sample only peripheralblood, although the vast majority of memory T cellsreside in tissue sites, including lymphoid tissues, intes-tines, lungs and skin (see below); and second, moststudies on human memory T cells use samples that areobtained from young or middle-aged adults, althoughthe majority of memory T cell responses are formedduring childhood from primary infections. However,recent conceptual and technological breakthroughsnow enable novel investigations of T cell responses inhumans. In this Review, we integrate these new studieswith previous findings from T cells isolated from healthyand diseased patients to assess our current knowledge
1Columbia Center for
Translational Immunology
and Department of
Microbiology and
Immunology, Columbia
University Medical Center,
650 West 168th Street,
BB1501, New York,
New York 10032, USA.2Department of Surgery,
Columbia University Medical
Center, 650 West 168th
Street, BB1501, New York
10032, USA.3National Cancer Institute,
National Institutes of Health,
Bethesda, Maryland 20892,
USA.
Correspondence to D.L.F.
e-mail: df2396@cumc.
columbia.edu
doi:10.1038/nri3567
Published online
13 December 2013
Human memory T cells: generation,compartmentalization andhomeostasisDonna L. Farber1,2, Naomi A. Yudanin1and Nicholas P. Restifo3
Abstract | Memory T cells constitute the most abundant lymphocyte population in the body
for the majority of a persons lifetime; however, our understanding of memory T cell
generation, function and maintenance mainly derives from mouse studies, which cannotrecapitulate the exposure to multiple pathogens that occurs over many decades in humans.
In this Review, we discuss studies focused on human memory T cells that reveal key properties
of these cells, including subset heterogeneity and diverse tissue residence in multiple mucosal
and lymphoid tissue sites. We also review how the function and the adaptability of human
memory T cells depend on spatial and temporal compartmentalization.
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mailto:df2396%40cumc.columbia.edu?subject=mailto:df2396%40cumc.columbia.edu?subject=mailto:df2396%40cumc.columbia.edu?subject=mailto:df2396%40cumc.columbia.edu?subject= -
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00 0
5 10 15 20
20 200
400
600
800
25 30 35 40
40TotalT
cells(%)
Age (years)
Infectiousdisease
hospitaliza
tionrate
(per10,000
individuals)
45 50 55 60
60
70 75 80
80
100Memory T cell
Memorygeneration
Memoryhomeostasis
Immuno-senescence
Circulating
memory T cell
Pathogensusceptibility
65
Memory homeostasis
The stable maintenance of
memory T cell numbers
through multiple mechanisms,
including continuous turnover,
responses to homeostatic
cytokines and non-cognate
T cell receptor interactions.
Immunosenescence
The decreased function of the
immune system with age. In
particular, the number of naive
T cells decreases as thymic
function decreases.
of human memory T cells. We describe recent studiesthat are beginning to investigate how memory T cellsare organized in human tissue sites, including their func-tional capacities and antigen specificities, and we discussthe implications of these insights for promoting in situimmunity in response to vaccines that use targetedtherapies. We also discuss the accumulation of memoryT cells over a lifetime and how compartmentalizationand specificity of memory T cells is maintained throughhomeostasis.
Memory T cell accumulation throughout life
The frequency of memory T cells undergoes dynamicchanges throughout an individuals lifetime that canbe divided into three phases: memory generation,memory homeostasis and immunosenescence (FIG. 1).At birth, all T cells in the peripheral blood are naive,
and memory T cells develop over time in response toexposure to diverse antigens. A marked increase inthe proportion of circulating memory T cells occursin the first decade of life, and memory T cells con-stitute up to 35% of circulating T cells by the end ofthe second decade of life9. During this initial memorygeneration phase, particularly during infancy andearly childhood, individuals have the highest suscep-tibility to pathogens, as measured by infectious dis-ease hospitalization rates10. The second phase, termedmemory homeostasis, begins in the third decade oflife, when circulating memory T cell frequencies reacha plateau and remain stable throughout adulthood11,12
(FIG. 1). Thymic output gradually decreases duringthis phase and T cell numbers are mostly maintainedthrough homeostatic cell turnover 13. Individualsin these middle years of life are less susceptible topathogens, as shown by the low hospitalization rateof infectious diseases10, and the immune responseis directed to homeostasis. After decades of stablememory T cell frequencies, the proportion and thefunctionality of memory T cells becomes altered dur-ing immunosenescence, starting at 6570 years ofage9,12,14. Immunosenescence also marks an increasedsusceptibility to pathogens that is partly caused byage-associated immune dysregulation and non-immune-related physiological decline. As immuno-senescence has recently been reviewed elsewhere14,15,we focus below on the first two phases: memorygeneration and homeostasis.
Memory T cell frequency in the blood is a markedunderestimate of the total frequency and numbers ofmemory T cells in the whole body. Estimates of thenumber of T cells in human tissues are 2 10 10in the
skin16,17, 1 1010in the lungs18, 3 1010in the intestines19and 20 1010in lymphoid tissues (that is, the spleen,the lymph nodes and the bone marrow)19. Therefore,peripheral blood T cells (510 109in human blood)represent only 22.5% of the total T cell complementin the body19, and memory T cells represent the pre-dominant T cell subset in mucosal sites, skin, spleen andbone marrow20. Early in infancy, T cells are observedto populate the intestines21and the lungs22, with 20% ofthese cells in the intestines showing a memory pheno-type in newborns21, perhaps owing to the antigens thatthey encountered in utero(see below). Recent studiesin human tissues (described below) have shown that,by the end of puberty, lymphoid tissues, mucosal sitesand the skin are predominantly populated by memoryT cells, which persist throughout adult life and whichrepresent the most abundant lymphocyte population inthe body11,23.
Memory T cell subsets and heterogeneity
Heterogeneity in peripheral blood.Memory T cells inhumans are classically distinguished by the expressionof the CD45RO isoform and by the lack of expressionof the CD45RA isoform (CD45RO+CD45RA)24,25.CD45RO+CD45RAT cells are now known to com-prise heterogeneous populations of memory T cellsubsets. Nearly 15 years ago, Sallusto, Lanzavecchia
and colleagues26first identified this heterogeneity inhuman peripheral blood on the basis of the expressionof the lymph node-homing CC-chemokine receptor 7(CCR7). Naive T cells uniformly express CCR7, whichreflects their predominant residence in lymphoid tissue,whereas memory T cells are subdivided into CD45RA
CCR7+central memory T (TCM
) cells, which trafficto lymphoid tissues, and CD45RACCR7effectormemory T (T
EM) cells, which can migrate to multiple
peripheral tissue sites. The authors also showed that TCM
cells produced more interleukin-2 (IL-2) than T
EMcells,
which in turn produced more effector cytokines, andthey proposed a differentiation model in which T
CMcells
Figure 1 | Memory T cell frequency, pathogen susceptibility and mortality
throughout human life. Memory T cells pass through three distinct phases: memory
generation, memory homeostasis and immunosenescence. Memory T cells are mostly
generated following antigen exposure during infancy, youth and young adulthood
(ages 020 years). Their levels subsequently plateau and are maintained through
homeostasis throughout adulthood (ages 3065 years), after which time they enter
the third stage and show senescent changes (age >65 years). Previous studies haveshown that there is an increase in the frequency of memory T cells in the blood (red
line) over time9,12. In the whole body, which includes the blood, intestines, lungs, skin,
liver, brain and lymphoid tissues, the overall frequency of memory T cells (black line)
also increases with age11. The increase in memory T cell frequency throughout the
body inversely correlates with a decreased susceptibility to pathogen infection
(dashed line), as calculated from infectious disease hospitalization rates (per 10,000
individuals) recorded from 1998 to 2006 in the United States from a total of
40,085,978 hospitalizations10.
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Naive T cell TSCMcell TCMcell TEMcell
TRMcell
TEff
cell
?
Death
Lymphoid tissues Peripheral tissues
Antigen exposure
are an intermediate stage in the differentiation of naiveT cells into T
EMcells in peripheral tissue sites27. The
existence of TCM
and TEM
cell subsets in lymphoid andperipheral tissue sites was confirmed in mouse mod-els28,29. The original model of functional memory T cellsubsets has since been revised to include a further char-acterization of human peripheral blood memory T cellsubsets in health and disease. An effector functionalcapacity is not confined to T
EMcells, as both T
CMand
TEM
cell subsets produce effector cytokines in responseto viruses, antigens and other stimuli3033, although T
CM
cells show a higher proliferative capacity30,34.The expression of additional surface markers, includ-
ing the death receptor CD95 (also known as FAS) andthe memory-associated marker CD122 (also known asIL-2R), in the context of naive-appearing T cells wasrecently found to delineate a new memory T cell subsetin humans35and mice36, designated stem cell memoryT (T
SCM) cells, which have superior survival potential
and efficiently engraft in allogeneic transplant models.In humans, T
SCMcells resemble naive T cells in that they
are CD45RA+CD45ROand they express high levelsof the co-stimulatory receptors CD27 and CD28, IL-7receptor -chain (IL-7R), CD62L and CCR7. T
SCM
cells have a high proliferative capacity and are both self-renewing and multipotent, in that they can further dif-ferentiate into other T cell subsets, including T
CMand
TEM
cells35,37. These properties define their stem cell-likecapacities35,38.
Elucidating the differentiation pathways for heter-ogeneous memory T cell subset development follow-ing naive T cell activation has been an area of active
debate and investigation. Although the lineage rela-tionship of human T cell subsets is difficult to deter-mine, a progressive differentiation pathway based onsignal strength and/or extent of activation, places naive,T
SCM, T
CMand T
EMcells in a differentiation hierarchy,
in which these cells function as precursors for effec-tor T cells3840(FIG. 2). Another model suggests that theT
EMand T
CMcell subsets derive from effector T cells,
with TEM
cells giving rise to TCM
cells. A third modelposits a divergent generation of effector, T
CMand T
EM
cell subsets (reviewed in REF. 41). Recent studies of thefate of individual T cells in mice during infection pro-
vides evidence that a single naive T cell can give riseto heterogeneous memory T cell populations followingactivation4244and supports a progressive differentia-tion model (FIG. 2). Moreover, these individual fates inmouse T cells can be determined at early times afteractivation as a result of asymmetrical cell division45.The mechanisms and the timing of human effector andmemory T cell fate determination remain undefined.
The heterogeneity of memory T cell subsets in
peripheral blood shows only a small fraction of the totalcomplexity of memory T cell distribution throughoutthe body. Seminal mouse studies showed that antigen-specific memory CD4+and CD8+T cells can populateand persist in multiple tissue sites long after virus orantigen was cleared28,29. Early studies of surgical explantsin humans showed that CCR7T
EMcells were the pre-
dominant memory T cell subset found in the intestinesand the lungs, whereas tonsils contained both T
CMand
TEM
cells46. This diverse tissue distribution of memoryT cells raised the question of whether they had just circu-lated through these tissues or whether they had becomeresident at these sites as a consequence of furtherdifferentiation.
In the past several years, mouse studies have estab-lished the existence of a new tissue-resident memory T(T
RM) cell subset as a non-circulating subset that resides
in peripheral tissue sites and, in some cases, elicits rapidin situprotective responses. Mouse CD4+T
RMcells can
be generated in the lungs from adoptive transfer of acti-vated (effector) T cells4or following respiratory virusinfection47, and are distinguished from splenic and cir-culating memory T cells by their upregulation of theearly activation marker CD69, their tissue-specific reten-tion in niches in the lungs47and their enhanced abilityto mediate protection against influenza virus infectioncompared to circulating memory CD4+T cells4. An
analogous non-circulating CD4+TRMcell subset hasbeen identified in the bone marrow of mice followingsystemic virus infection and these cells show enhancedhelper functions48.
Memory CD8+T cells were initially found to persistas circulating and resident populations in lymphoidtissues, lungs and mucosal tissues in mice49. CD8+T
RM
cells generated following infection have subsequentlybeen identified in multiple mouse tissues, includ-ing the skin50,51, vaginal mucosa52,53, intestines49,54,55,lungs47,56and even the brain57. CD8+T
RMcells are col-
lectively distinguished from splenic and circulatingmemory CD8+T cells by their increased expression
Figure 2 | A model for the generation of human memory T cell subsets.
A schematic model for the differentiation of circulating and tissue-resident memory
T (TRM
) cell subsets is shown. The progressive differentiation of the three major
circulating subsets stem cell memory T (TSCM
) cells, central memory T (TCM
) cells
and effector memory T (TEM
) cells from activated naive T cells is shown relative to
the extent of antigen exposure. Effector T (TEff
) cells represent terminally
differentiated cells, and death is one outcome of increased antigen exposure and
proliferation. Naive, TSCM
and TCM
cells circulate and migrate to lymphoid tissue,
whereas TEM
and TEff
cells are the subsets of T cells that have the capacity to traffic toperipheral tissues. T
RMcells in peripheral tissue sites may derive from either T
EMor
TEf
cells that migrate to these sites through tissue-specific factors. It is possible
that TCM
cells could develop into TRM
cells in lymphoid sites (dashed arrow). TRM
cells
in the peripheral compartments are probably terminally differentiated as they do
not circulate or convert to other memory T cell subsets.
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of CD69 (similarly to CD4+TRM
cells) and by theirexpression of the epithelial cell-binding E7 integrin(also known as CD103)20,52,5860. Protection by CD8+T
RMcells has been shown to occur in the skin of mice
in response to intradermal herpes simplex virus 2(HSV2) infection6163and to HSV1 and HSV2 infec-tions at the vaginal mucosa52,53. These mouse stud-ies indicate that T cell-mediated memory responses,and in particular those with high protective capacity,are highly compartmentalized in tissue sites, whichnecessitates the study of memory T cell populations inanatomical sites other than the blood.
Although TRM
cells are less well characterized inhumans than in mice, recent studies have started todefine these populations by sampling tissues fromorgan donors11 and from surgical explants18,50. Awhole-body analysis of T cells in multiple lymphoidand mucosal sites revealed that memory CD4+T cellspredominate throughout the body and persist asCCR7+or CCR7subsets that are localized to lymphoidtissues and mucosal sites, respectively. Conversely,
memory CD8+T cells were shown to persist mainly asCCR7subsets in all sites, with low numbers of CD8+T
CMcells in lymphoid tissues and negligible numbers of
these cells in other sites11. Importantly, most memoryT cells in human mucosal, lymphoid and peripheraltissue sites such as the skin express the putative T
RMcell
marker CD69 (REFS 1416,20,58), whereas circulatingblood memory T cells uniformly lack CD69 expres-sion11. Taken together, these studies suggest that CD69+T
RMcells are present as major populations in human
mucosal and peripheral tissue sites, similarly to theircounterparts in mice. In contrast to mouse lymphoidmemory T cells, a large proportion of T
EMcells in human
lymph nodes and spleen also express CD69 (REF. 11),which suggests that T
RM cells may also be present
in lymphoid tissues.The pathways and the mechanisms that are respon-
sible for the generation of TRM
cells remain unknownand are important areas for future studies. Mouse stud-ies suggest that T
RMcell generation occurs within tis-
sue sites from either activated effector T cells and/orT
EMcell precursors that migrate to tissue sites47,64(FIG. 2).
We propose that the pathway to human TRM
cell devel-opment involves both migration and tissue-specificfactors, as suggested by the examination of T
RMcell
distribution and properties11,16,18(FIG. 3). Bloodbornememory T
CMand T
EMcell subsets can enter certain tis-
sue sites such as the spleen, lungs, lymph nodes andbone marrow at a low frequency, but are not markedlyrepresented in the skin and intestines (T
SCMcells are
present in the lymph nodes in non-human primates65but their distribution in humans is not known). CD4+T
RMcells (CCR7CD69+) and CD8+T
RMcells expressing
CD103 are the predominant T cell subsets in the lungs,intestines, skin and bone marrow11,20,66. Lymphoid tis-sues contain T
CMcells and T
EMcells, some of which also
express CD69 but not CD103 (REF. 11). It is not knownwhether additional markers define lymphoid T
RMcells
and/or whether CD69+TEM
cells in lymphoid tissue aretrue resident memory cells.
Human TRM
cells also have tissue-specific properties(FIG. 3), which suggests that they have in situ influences.T
RMcells in the skin express cutaneous lymphocyte anti-
gen (CLA; a glycoform of PSGL1) and the skin-homingchemokine receptors CCR4 and CCR10 (REFS 16,67,68);memory T cells in the small intestines and colon expressthe gut-homing receptor CCR9 (REF. 69)and 47 inte-grin70; and memory T cells in the lungs upregulateCCR6 expression18. There is also evidence for crosstalkbetween mucosal sites such as the lungs and the intes-tines71. Migration of T
EMcells to the bone marrow in
mice requires expression of 21 integrin (also knownas VLA2)64, but it is not known whether human bonemarrow T
RMcells have a similar requirement. This dif-
ferential chemokine receptor and/or integrin expressionmay derive from activated or effector populations thatenter the site72,73, or alternatively these proteins might beupregulated during the homeostasis of naive or memoryT cells74. This identification of human T
RMcells with tis-
sue-specific signatures suggests that there is anatomicalcontrol of memory T cell generation in humans.
Functional capacity of heterogeneous subsets. Theextensive phenotypic and tissue complexity among het-erogeneous memory T cell subsets suggests that thereis a corresponding functional heterogeneity. Mouse andhuman CD4+T cells of a non-regulatory lineage are sub-divided into functional subsets the most prevalentbeing T helper 1 (T
H1) cells that produce interferon-
(IFN), IL-2 and tumour necrosis factor (TNF), TH
2cells that secrete IL-4, IL-5, IL-10 and IL-13, andT
H17 cells that produce IL-17. CD8+T cells are not typi-
cally subdivided into functional subsets and generallyproduce IFN and TNF, and express cytolytic markerssuch as perforin and CD107. In the peripheral blood ofhealthy individuals, most circulating memory CD4+andCD8+T cells produce IFN, IL-2 and/or TNF follow-ing short-term stimulation, and only low numbers ofIL-4-producing, IL-10-producing and IL-17-producingmemory CD4+T cells are observed35,75. Human periph-eral blood T
EM, T
CMand T
SCMcell populations differ in
the relative proportion of cells that produce IL-2, IFNand/or TNF: T
EMcells have the highest proportion of
IFN-producing and TNF-producing cells and the low-est proportion of IL-2-producing cells; T
SCMcells have
the lowest proportion of IFN-producing cells andmore IL-2-producing cells compared with T
EMcells;
and the TCM
cell population has the highest frequency
of IL-2-producing cells with proportions of IFN-producing and TNF-producing cells that are intermedi-ate between the T
SCMand T
EMcells35,38(FIG. 3). Variations
in the expression of chemokine receptors have also beenassociated with different functional capacities of humaneffector T cells; for example, in vitropolarized T
H1 cells
were found to express CXC-chemokine receptor 3(CXCR3), CCR2 and CCR5, whereas T
H2-polarized
cells expressed CCR3 and CCR4 (REF. 76). However, theexpression of these chemokine receptors can be tran-sient depending on the microenvironment77and doesnot consistently delineate functional subsets amongresting memory T cells78.
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a
b
Bone marrow Blood
Intestines
CCR7
CCR9 47 integrin
21 integrin
CCR4 CCR10 CLA
CCR6
Lymph node
Lungs
TCMcell TCMcell
TCMcell
TCMcell
TRMcell
TRMcell
Lymph nodeSkin
TCMcell
TCMcell
TRMcell
TRMcell
TRMcell
TRMcell
CD103+
TRMcell
CD103+
TRMcell
CD103+
TRMcell
CD103+
TRMcell
TRMcell
TEMcell
TEMcell
TEMcell
TEMcell
TEMcell
TEMcell
TSCMcell
TSCMcell
TSCMcell
TRMcell TEMcell
CD45RA +
+
+
+
+++
+
++
++
+++++
+++
+++
+
+/
+++
+++
+
+
+/
+++
+++
CCR7
CD69
CD103
IL-2
IFN
TNF
Circulating memory T cells Tissue-resident memory T cells
Spleen
Figure 3 | Schematic of memory T cell heterogeneity in the blood and in tissues. a | The tissue distribution and the
migration patterns of the major human memory T cell subsets are shown, including the three major circulating populations
stem cell memory T (TSCM
) cells, central memory T (TCM
) cells and effector memory T (TEM
) cells as well as the
tissue-resident memory T (TRM) cell populations in multiple sites, including the CD8+TRMcells that are defined by expression
of CD103 (CD103+TRM
cells) and that are associated with mucosal sites and the skin. The individual sites are defined as the
circulation (red), of lymphoid origin (grey) or as peripheral tissues (yellow). Circulating TSCM
, TCM
and TEM
cell subsets migrate
from the blood and circulate through the spleen and the lungs, where they can be primed to migrate to the intestines71.
They also migrate via the lymphatics and efferent vessels to the lymph nodes. TRM
cells predominate in the skin, the lungs,
the bone marrow and the intestines, but may also be present within the CD69+TEM
cell subsets in the spleen and the lymph
nodes (not shown). The expression of certain chemokine receptors and/or integrins is associated with T cell migration
and/or residence in the lymph nodes (CC-chemokine receptor 7 (CCR7)), the skin (CCR4, CCR10 and cutaneous
lymphocyte antigen (CLA)), the intestines (CCR9 and 47 integrin), the lungs (CCR6) and the bone marrow (21 integrin).b|Key phenotypic and functional properties of circulating and resident subsets are shown; CD45RA and CCR7 distinguish
circulating memory T cell subsets, and CD69 (and CD103) expression delineate TRM
cells. Memory T cell subsets can
produce similar types of recall cytokines, such as interleukin-2 (IL-2), interferon-(IFN) and tumour necrosis factor (TNF),but they differ in the extent and the quality of these responses. +, low expression levels; ++, medium expression levels;
+++, high expression levels. Dashed lines indicate putative migration patterns from mouse studies.
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ELISPOT
(Enzyme-linked
immunosorbent spot).
An antibody capture-based
method for enumerating
specific CD4+and CD8+T cells
that secrete a particular
cytokine (often interferon-).
MHC tetramer
A method of visualizing
antigen-specific T cells by flow
cytometry. Typically, four MHC
molecules with their associated
peptides are held together by
streptavidin (that has four
binding sites for biotin), which
is attached to the tail of the
MHC molecule. These four
peptideMHC complexes
(tetramers) can bind to
peptide-specific T cell
receptors. The streptavidin
molecules are often labelled
with a fluorochrome so that
binding can be assessed byflow cytometry.
The functional capacities of human TRM
cells arebeginning to be defined. Overall, memory CD4 +and CD8+T cells in lymphoid and mucosal tissuesobtained from healthy individuals show rapid IL-2and IFN production, respectively, when nonspecifi-cally activated with the mitogens phorbol 12-myristate13-acetate (PMA) and ionomycin11. It was previouslydetermined that individual circulating memory T cellscan produce multiple cytokines, and the presence ofthese multifunctional or polyfunctional memoryT cells correlated with superior recall and protectivememory responses79. There is emerging evidence thatT
RMcells can be multifunctional and that they have
qualitative functional differences. Human bone mar-row T
RMcells are polyfunctional for effector cytokines
and cytolytic molecules48,80, a substantial propor-tion of human lung T
RMcells produce multiple pro-
inflammatory cytokines18, and human intestinal TRM
cells are also polyfunctional11. However, other func-tions seem to be confined to specific subsets and/ortissue sites. IL-17 is produced by a subset of CD4+
TRMcells in mucosal sites, particularly in intestinesof healthy individuals11, by CCR6+memory T cells inperipheral blood81,82and also by a subset of CD161 +T cells in inflamed tissue, such as the skin of patientswith psoriasis83. A subset of skin memory CD4+T cellscan produce IL-22 (but not IL-17) when cloned andexpanded ex vivo84, and IL-22-producing T cells havealso been identified in inflamed skin in patients withpsoriasis 85. Thus, although predominant memoryT cell functions, such as IFN production, are broadly
distributed among multiple memory T cell subsets andtissues, T
RMcells in t issue sites can adopt multiple or
distinct functional attributes that may also depend ontissue-specific inflammation.
Antigen specificity and diversity
Specificity in the adaptive immune response is intricatelylinked to the establishment and persistence of memoryT cells that record previous antigen experiences viaspecific T cell receptors (TCRs). In mice, the develop-ment of memory T cells in response to viral pathogensis marked by extensive clonal expansion of virus-specificT cells, followed by the contraction and death of >90%of activated or effector T cells, as well as the long-termpersistence of virus-specific memory T cells at variablefrequencies (10% of the total number of T cells)depending on the virus2,86. These mouse models aregenerally used to investigate memory T cell develop-ment and responses to one type of virus in otherwisesterile conditions. By contrast, in humans, antigen-specific memory T cells are generated and dynamically
maintained as a heterogeneous T cell population in thecontext of thousands of different pathogens that areintroduced at various stages of life. Therefore, assess-ing the physiological importance of antigen-specificmemory T cells in humans has proved challenging.
Pathogen-specific memory generation and maintenance.Our ability to measure the frequency of human antigen-specific memory T cells has increased in accuracy andsensitivity from classical functional recall assays tocytometry-based methods (BOX 1). The assessment ofhuman antigen-specific memory T cells has mostlyoccurred in the context of virus infections that are ubiq-uitous in healthy humans, including acute infectionswith influenza virus and chronic infections with virusessuch as cytomegalovirus (CMV) and EpsteinBarr virus(EBV). Memory T cell responses to these viruses are gen-erated as a result of a productive immune response thateffectively controls the virus. Human T cell responsesin chronic HIV infection have been extensively studied;however, mechanisms for their generation and main-tenance are more complex, as memory T cells are thetargets for chronic infection and virus persistence8789,and HIV is not cleared by the immune system in mostindividuals (reviewed in REFS 9092).
Cross-sectional studies of memory T cell frequencyin different age groups show that most virus-specific
memory T cells are generated early in life. CongenitalCMV infection was shown to result in the genera-tion of virus-specific memory CD8+T cells in utero93.Furthermore, in a large cohort study of children andadults, CMV-specific CD8+T cells were detected inthe blood of infants and their frequency remainedstable throughout early childhood and young adult-hood94. Memory T cells that are specific for adeno-
virus are detected in early childhood and progressivelyincrease in frequency until the age of 10 years, fromwhich time they remain at a constant level throughoutadulthood31. In addition, influenza virus-specific T cellsare detected in children at levels that are comparable
Box 1 | Approaches to analyse antigen-specific T cell memory
The techniques for examining antigen-specific T cell responses have increased insensitivity and specificity in recent years. The classical limiting dilution assay requires
ex vivoantigen-driven expansion of human T cell populations, but this approach is
imperfect because non-proliferating T cell clones are under-represented. The
development of the ELISPOT(enzyme-linked immunosorbent spot) assay has more
recently provided a sensitive but robust functional method to detect antigen-specific
memory T cells using their rapid production of effector cytokines, and has enabled
their precise quantification without the need for antigen-driven population
expansion.
The development of MHC tetramerreagents148facilitated the visualization and the
quantification of epitope-specific T cells solely on the basis of T cell receptor (TCR)
specificity, although this approach lacks a functional readout. TCR staining with
tetramers, pentamers or MHC multimers has facilitated a more sensitive estimation of
memory T cell specificity in humans compared with direct functional recall responses to
antigens as measured by ELISPOT or limiting dilution assays149,150. Moreover, new
techniques to enrich antigen-specific T cells using labelled tetramer reagents andsecondary binding reagents coated to magnetic beads115have facilitated the detection
of rare antigen-specific T cell populations, even among naive T cell populations that
have not undergone in vivoexpansion.
The most recent technical advance in antigen-specific T cell detection is achieved
through the use of cytometry by time-of-flight mass spectrometry (CyTOF), which
applies the technique of mass cytometry by using antibodies labelled by lanthanides
with different atomic masses, facilitating >50 parameters to be investigated on single
cells151without the problems of compensation that occur in multiparameter flow
cytometry. Coupling different mass labels to tetramer reagents facilitates the
combinatorial assessment of >50 TCR specificities in a single sample152. The use of these
new technologies makes the assessment of T cell epitope specificities from small
clinical biopsy samples possible, which will be essential for the future diagnostic
application of TCR antigen specificities in immune monitoring.
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to those observed in adults95,96. Taken together, theseresults suggest that, despite the overall increase in cir-culating memory T cells over a lifetime (FIG. 1), memoryT cells that are generated against ubiquitous patho-gens increase in frequency in early life and are stablymaintained throughout adulthood.
The ability to observe pathogen-specific humanmemory T cell development throughout the processesof clonal expansion and contraction is not readilyaccomplished;however, prospective infection and
vaccine studies have provided novel glimpses into thisprocess. Circulating T cells that are specific for EBVor for influenza virus underwent clonal expansion,contraction and persisted as memory T cells follow-ing acute infection9799. Similarly, the administrationof yellow fever and smallpox vaccines, which bothconsist of live viruses, stimulated robust CD8+T cellclonal expansion, contraction and memory formationthat is measurable in the peripheral blood 100. However,there was no discernible increase in the frequency ofcirculating virus-specific T cells following acute infec-
tion with rotavirus101, which is a gastrointestinal virus,or with the lung pathogen respiratory syncytial virus(RSV)102,103. This variability in observing memory T celldevelopment in human blood may be due to inefficientmobilization of memory responses during infection104and/or compartmentalization of pathogen-specificresponses at the infected site.
Several studies have shown that there is a highergeneration and maintenance of virus-specific effectorand memory T cells in tissues compared with the cir-culation. Intradermal immunization with purified pro-tein derivative (PPD) ofM. tuberculosisresulted in theproliferation of antigen-specific T cells in the skin butnot in the blood105. Similarly, cutaneous challenge with
varicella zoster virus resulted in memory T cell accu-mulation in the skin106, which suggests that the forma-tion of memory T cells may occur at distinct sites. Lungtissue was found to contain an increased frequency ofinfluenza virus-specific memory CD8+T cells com-pared to the blood107,108and the spleen47, and influenza
virus-specific T cells in human lungs were found tohave a T
RMcell phenotype (that is, CD69+CD103+)47,109.
CD8+T cells that are specific for HSV2 were found topersist in genital skin, but not in skin from other bodyregions110, which suggests that skin T
RMcells are locally
maintained. Similarly, memory CD4+T cells that arespecific for astrovirus, which is a common enteropath-
ogenic virus, were detected in the small intestines111.Taken together, these results suggest that compart-mentalization of pathogen-specific memory T cellresponses are preferentially maintained at the sites ofinitial effector T cell recruitment. These findings alsoindicate that accurate assessment of pathogen-specificmemory T cell responses probably requires samplingof the initial infection site.
Memory T cell cross-reactivity.Despite their specific-ity, human memory T cells cross-react with antigenicepitopes that have not previously been encountered,which is possibly due to intrinsic properties of TCR
recognition112and to the range and the breadth ofhuman antigenic experience. Memory CD4+and CD8+T cells that were specific for unique epitopes of avianinfluenza strain H5N1 were detected in healthy indi-
viduals that were not exposed to H5N1 infect ion, asassessed by serology113,114. In addition, HIV-specificmemory T cells have been identified in HIV-negativeindividuals115. Virus-specific memory T cells alsocross-react with alloantigens, autoantigens and unre-lated pathogens116,117: EBV-specific human memoryT cells generated in HLA-B8 individuals showed allo-geneic cross-reactivity to HLA-B44 (REF. 118), and influ-enza virus-specific and HIV-specific memory CD4+T cells recognized epitopes from unrelated microbialpathogens115. Furthermore, T cells that were specificfor the autoantigen myelin basic protein (MBP) recog-nized multiple epitopes from viral and bacterial path-ogens117,119. This cross-reactivity may enable memoryT cells to mediate protection without an initial disease a phenomenon known as heterologous immunity120.Heterologous immunity has been shown to occur
in humans; cross-reactive influenza virus-specificT cells were shown to be activated and to proliferateby EBV infection121.The role of T cell cross-reactivityin determining how T cell subsets may be compart-mentalized in tissue sites is not known, but couldbe an important mechanism for their homeostaticmaintenance (see below).
Role of microbiome in generating memory T cells.Mucosal sites and the skin harbour resident bacteriaand viruses, which are collectively referred to as themicrobiome. Humans are exposed to >2,000 microbialspecies8, of which only a small proportion are patho-genic. It has been suggested that the very purpose ofimmune memory in vertebrates is to preserve properimmune homeostasis with commensal microorgan-isms8. Studies in mouse models show that the presenceand the composition of the microbiome are crucial inpromoting appropriate immune responses to patho-gens and in maintaining proper immune homeostasis(reviewed in REF. 122). Whether the species of com-mensal microorganisms that are present in certainsites influence the type of memory T cells that residethere is not known. In a limited study investigating thereactivity of T cells expanded from the blood and fromintestinal biopsy samples of two patients to endog-enous bacterial flora, more bacteria-reactive T cells
clones were isolated from the intestines than from theblood123, which suggests that intestinal T cells may havebiased cross-reactivity to intestinal flora. Althoughmemory T cells that are specific for commensal bac-teria have recently been detected in mice124, they areassociated with pathogenic infection of the intestinesand could be a consequence of dysregulated immunityin inflammatory bowel disease. By contrast, in humans,memory T cells survive far longer and are exposed tomore antigens during their lifetime, and therefore com-mensal microorganism-specific responses may be partof the healthy immune balance between the microfloraand the indigenous T cells.
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Infant
Skin HSV, VZV and microbiota
Lymph nodes Vaccinia virus
Spleen EBV
Blood
Age
CMV
YouthYoungadult Adult
Localization Frequency Specificity
Naive T cell TCMcell TEMcell TRMcell
LungsInfluenza virus
and microbiota
Intestines Rotavirus and microbiota
Telomeres
Regions of highly repetitive
DNA at the end of linear
eukaryotic chromosomes. They
protect the ends of the
chromosome from shortening
following replication.
Human memory T cell homeostasis
Specific clones of memory T cells that express a uniqueTCR can persist for decades in vivo. Human memoryT cell longevity is clearly shown by studies indicatingthat memory T cells specific for vaccinia virus theaetiological agent of smallpox, which was eradicatedfour decades ago persisted in individuals who hadbeen vaccinated 2570 years previously125. However,the mechanisms for memory T cell maintenance inhumans remain unclear. In mouse models, the long-term requirements for T cell maintenance and homeo-stasis have been defined using mice that are deficientfor various cytokines and cytokine receptors, for MHCmolecules and/or for components of the TCR signalling
cascade (reviewed inREF. 126). These studies establishedthat virus-specific memory CD8+T cells do not requireantigens or MHC molecules for their maintenance, butrather that they rely on IL-15 for homeostasis and IL-7for survival. By contrast, these studies showed that mem-ory CD4+T cells require TCR signalling and/or MHCclass II molecules for their functional maintenanceand homeostasis127129.
An elegant approach to probe human memory T cellturnover or longevity is to administer deuterated wateror deuterated glucose to volunteers and, subsequently,to examine the incorporation of deuterium by T cellsin vivo130,131. The calculated half-life of human T cellsusing this approach was found to vary according tothe type of labelling, the limited sampling of peripheralblood, the timing of sampling and the mathematicalalgorithm132. On average, human naive T cells have alonger half-life than memory T cells (18 years com-pared with 112 months, respectively)132; CD4+T cellshave a shorter half-life than CD8+T cells; and T
EMcells
have a shorter half-life than TCM
cells133. Compared with
naive T cells, human memory T cells also have shortertelomeresin individuals of all ages134, which indicatesthat they have a more extensive replicative history.These studies suggest that memory T cells in the circu-lation are partly maintained by continuous homeostaticturnover. Turnover and replicative history of humanmemory T cells in tissue compartments remains com-pletely uninvestigated and will be important to assessT
RMcell stability.Transcriptome, epigenetic and deep-sequencing
analysis of human memory T cells provide new evi-dence about the mechanisms that are responsible formemory T cell longevity135,136and the potential roleof TCR and cytokine signals in this process. Humanmemory CD4+and CD8+T cells show transcriptionalupregulation of genes that encode TCR-coupled acti-
vation markers compared with naive T cells, includingmultiple MHC class II molecules, chemokine recep-tors, CD95 and effector molecules135. Moreover, activa-tion-induced epigenetic changes in the loci of effectorcytokine genes are maintained in circulating humanmemory CD8+T cells135,137. Deep sequencing of TCRgenes revealed that there are conserved clonotypes andreduced diversity among human memory T cell sub-sets138,139. Taken together, these findings implicate tonicTCR signalling in human memory CD4+and CD8+T cell maintenance, potentially as a result of cross-
reactivity with self antigens, environmental antigensand/or resident commensal organisms. Requirementsfor cytokine signals in this maintenance are not clearlydefined, although individuals who have mutations inthe cytokine-induced transcription factor signal trans-ducer and activation of transcription 3 (STAT3) havereduced memory T cell frequency and responses140.Whether requirements for T
RMcell maintenance differ
according to the tissue site is not known; for example,memory T cells may be preferentially maintained bycross-reactive TCR-mediated interactions with micro-bial antigens at mucosal sites as a result of the highantigen density, whereas those in the blood, lymphoid
Figure 4 | Model for the compartmentalization of antigen-specific memory
T cell subsets in space and time. The relative naive and memory T cell subset
frequencies are shown in the circulation and the peripheral sites, as well as at different
stages of life (infant, 02 years of age; youth, 214 years of age; young adult, 1525
years of age; adult, >25 years of age). The schematic also shows the biased specificity
for certain pathogen-derived antigens that has been observed in specific tissue sites,
including antigens derived from cytomegalovirus (CMV) in the blood, EpsteinBarr
virus (EBV) in the spleen, vaccinia virus in the lymph nodes, influenza virus in the lungs,
rotavirus in the intestines, and herpes simplex virus (HSV) and varicella zoster virus
(VZV) in the skin. In addition, the specificities of some memory T cells at mucosal sites
(for example, the lungs, intestines and skin) are biased for antigens from the
microbiota. At birth, there is a preponderance of naive T cells in the circulation, and an
abundance of mucosal microbial antigens are encountered during infancy, which
results in seeding of mucosal sites with effector memory T (TEM) cells that are specificfor mucosal pathogens; these cells could develop into tissue-resident memory T (T
RM)
cells in situ. Although cell numbers in human skin have not been quantified in
individuals of different ages, infant skin is likely to contain few T cells based on
estimates from older children. During childhood, exposure to the ubiquitous
pathogenic and non-pathogenic microbial species occurs in each site and new
memory T cells are formed, which are partitioned as TRM
cellsin the skin and mucosal
sites, and as central memory T (TCM
) cells in the lymphoid tissues. This partitioning of
antigen-specific memory T cell subsets in tissues is maintained during adulthood, with
more TEM
and TCM
cell subsets gradually accumulating in the circulation and the lymph
nodes, which could potentially replenish and/or convert to TRM
cells that are lost
through attrition. Data showing the relative frequencies of each T cell subset in each
tissue site for youths to adults are compiled from REF. 11, and are extrapolated for
infants on the basis of REFS 21,22.
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tissue, spleen and bone marrow may be preferen-tially maintained through responses to homeostaticcytokines such as IL-7 or IL-15, which are expressedat these sites64.
Antigen-specific memory T cells in space and time. Suggestions have been made about how T cell subsetsand their specificities for ubiquitous microbial antigensare distributed in space (from the circulation to theperipheral tissue sites) and time (from infancy to oldage) (FIG. 4). T
EMand T
RMcell compartmentalization in
mucosal and peripheral tissue sites is initiated duringinfancy and is stably maintained throughout life. T
RMcell
populations in these sites may be enriched for cells spe-cific for pathogenic and non-pathogenic microbial spe-cies that populate or that infect these tissues. Dynamicchanges occur in the circulation and in the lymphoidtissue, including the reduction in naive T cells and theincrease in T
CMand T
EMcell subsets that occurs with
increasing age. Circulating TEM
cell populations maybe enriched for cells that are specific for chronic and
systemic pathogens, but not for those that are specificfor microbiota in tissues. We hypothesize that thissequestration of memory T cell specificities in distinctanatomical compartments could be a mechanism tostabilize and to preserve pathogen-specific memoryT cells, and to maintain immune homeostasis in thebody. Through additional tissue sampling and integra-tion of large data sets using computation and statisticalapproaches, it will be possible in future studies to directlytest this model (FIG. 4)and to map the organization ofT cell subsets and their specificities within the humanbody throughout life.
Implications for vaccines
The induction of memory T cells through vaccinationhas great potential to provide efficacious protectiveimmunity to multiple types of pathogens, includ-ing viral, intracellular bacterial and parasitic infec-tions, because of their broad specificity for internaland conserved pathogen epitopes, their residence indiverse sites of infection and their longevity. Immuneprotection in the context of the vaccines that are cur-rently used is mostly associated with the generation ofneutralizing antibodies, and the potential of memoryT cells to mediate protection has not been realized141.Several recent human challenge studies have showna correlation between protection and the presence
of memory T cells. One such study using influenzavirus found a direct correlation between the presenceof virus-specific memory CD4+T cells and reducedillness to influenza virus challenge142. In addition,the generation of circumsporozoite protein (CSP)-specific memory CD4+T cells using a malaria vaccinecorrelated with protective antiparasite immunity143.Multifunctional circulating memory CD4+T cells aresimilarly associated with HIV-infected non-progres-sors79. Therefore, although the generation of memoryCD8+T cells is often the focus of mouse studies ofimmune protection, memory CD4+T cells may also bea relevant subset to target in humans.
The consideration of the anatomical location of vac-cine administration seems to be crucial in the design of
vaccines to promote the generation of pathogen-specificmemory T cells in the right place and at the right time.Administering a vaccine or an attenuated pathogen atthe site of infection in the skin, the lungs, or the rectalor genital mucosal surfaces could enhance the generationof T
RMcells in vivo. Studies in mice have tested a prime
and pull strategy, in which pathogen-specific T cells areprimed using systemic vaccines and are then specificallyrecruited to a tissue site through the local administrationof chemoattractants53. In humans, the introduction of thesmallpox vaccine through skin scarification promoteslocal T cell responses and the long-term persistence of
vaccinia virus-specific memory CD4+T cells23,125. Thereare also promising results from HIV vaccine studies innon-human primate models using CMV-mediated vec-tors to promote the polyclonal generation of T
EMcells to
multiple epitopes144. HIV subunit vaccination using theseCMV vectors administered through multiple routes leadsto T
EMcell generation and population in mucosal and lym-
phoid sites, and to the development of lasting protectiveimmunity145,146. These studies show that adjusting theroute and the mode of immunization can facilitate mem-ory T cell-mediated protective immunity to intractablepathogens.
Timing is another important consideration formemory T cell generation and for vaccine design.Memory T cells that are generated early in life aremaintained at a measurable frequency throughout ahealthy adulthood, as shown in studies of the periph-eral blood31,94, which suggests that inducing memoryT cell generation at an early stage of life, when fewermemory T cells clones are present, enables these cells toestablish a niche for long-term persistence. Peripheraltissues have low numbers of memory T cells at birth butbecome populated by memory T cells by early child-hood (see above), which indicates that site-specific vac-cines could promote effective tissue targeting at earlystages of life. Other considerations, such as targetingtissue dendritic cells for the development of protectiveimmunity at specific sites71, and the co-administrationof immunomodulators to enhance memory T cellgeneration147, could be integrated into the design of
vaccines to generate durable in situT cell immunity.
Conclusions and perspectives
Improved and more sensitive methods to determine the
function and the antigen specificity of memory T cells,combined with high-throughput approaches, enable us todefine the molecular landscape of human immune cells.When combined with human tissue and blood samples,we have an unprecedented opportunity to obtain a morecomprehensive understanding of the immune systemin the context of the human lifespan, which is not pos-sible in animal models. Future studies that investigatesite-specific immune responses should focus on under-standing how memory T cells are generated in early lifeand on clarifying the role of the microbiome in theseprocesses to identify novel strategies to promote effectiveimmunoregulation and pathogen-specific immunity.
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1. Remakus, S. & Sigal, L. J. Memory CD8+T cell
protection.Adv. Exp. Med. Biol. 785, 7786
(2013).
2. Wherry, E. J. & Ahmed, R. Memory CD8 T-cell
differentiation during viral infection.J. Virol. 78,
55355545 (2004).
3. Teijaro, J. R.et al.Costimulation modulation
uncouples protection from immunopathology in
memory T cell responses to influenza virus.
J. Immunol. 182, 68346843 (2009).
4. Teijaro, J. R.et al.Cutting edge: tissue-retentive lung
memory CD4 T cells mediate optimal protection torespiratory virus infection.J. Immunol. 187,
55105514 (2011).
This study identifies the retention of CD4+TRM
cells
in mouse lungs and shows that lung TRM
cells have a
superior protective capacity against influenza virus
infection compared with circulating spleen memory
CD4+T cells.
5. Teijaro, J. R., Verhoeven, D., Page, C. A., Turner, D. &
Farber, D. L. Memory CD4 T cells direct protective
responses to influenza virus in the lungs through
helper-independent mechanisms.J. Virol. 84,
92179226 (2010).
6. Khader, S. A.et al.IL-23 and IL-17 in the
establishment of protective pulmonary CD4+
T cell responses after vaccination and during
Mycobacterium tuberculosischallenge.
Nature Immunol. 8, 369377 (2007).
7. Anthony, R. M.et al.Memory TH2 cells induce
alternatively activated macrophages to mediate
protection against nematode parasites. Nature Med.
12, 955960 (2006).
8. McFall-Ngai, M. Adaptive immunity: care for the
community. Nature 445, 153 (2007).
9. Cossarizza, A.et al.CD45 isoforms expression on
CD4+and CD8+T cells throughout life, from
newborns to centenarians: implications for T cell
memory. Mech. Ageing Dev. 86, 173195 (1996).
This paper is an early survey of memory T cell
frequencies in peripheral blood throughout the
human lifespan.
10. Christensen, K. L.et al.Infectious disease
hospitalizations in the United States. Clin. Infect. Dis.
49, 10251035 (2009).
11. Sathaliyawala, T.et al.Distribution and
compartmentalization of human circulating and tissue-
resident memory T cell subsets. Immunity 38, 187
197 (2013).
This study describes a whole-body analysis of T cell
subsets in the blood and in multiple lymphoid and
mucosal sites from individual organ donors. It
identifies how memory T cell subsets aredifferentially compartmentalized in tissue sites and
that this compartmentalization is remarkably
conserved between diverse individuals.
12. Saule, P.et al.Accumulation of memory T cells from
childhood to old age: central and effector memory
cells in CD4+versus effector memory and terminally
differentiated memory cells in CD8+compartment.
Mech. Ageing Dev. 127, 274281 (2006).
This paper is an excellent survey of peripheral
blood T cell subsets in a large cohort of individuals
from birth to old age.
13. den Braber, I.et al.Maintenance of peripheral naive
T cells is sustained by thymus output in mice but not
humans. Immunity 36, 288297 (2012).
14. Goronzy, J. J. & Weyand, C. M. Understanding
immunosenescence to improve responses to vaccines.
Nature Immunol. 14, 428436 (2013).
15. Nikolich-Zugich, J. & Rudd, B. D. Immune memory
and aging: an infinite or finite resource? Curr. Opin.
Immunol. 22, 535540 (2010).16. Clark, R. A.et al.The vast majority of CLA+T cells are
resident in normal skin.J. Immunol. 176, 4431
4439 (2006).
17. Clark, R. A.et al.A novel method for the isolation of
skin resident T cells from normal and diseased human
skin.J. Invest. Dermatol. 126, 10591070 (2006).
18. Purwar, R.et al.Resident memory T cells (TRM
) are
abundant in human lung: diversity, function, and
antigen specificity. PLoS ONE. 6, e16245 (2011).
The study describes the phenotype and the
functional properties of human TRM
cells in lung
tissue.
19. Ganusov, V. V. & De Boer, R. J. Do most lymphocytes
in humans really reside in the gut? Trends Immunol.
28, 514518 (2007).
This study provides a novel quantitative
assessment of human T cell numbers in mucosal
and lymphoid tissues.
20. Mueller, S. N., Gebhardt, T., Carbone, F. R. &
Heath, W. R. Memory T cell subsets, migration
patterns, and tissue residence.Annu. Rev. Immunol.
31, 137161 (2013).
21. Bunders, M. J.et al.Memory CD4+CCR5+T cells are
abundantly present in the gut of newborn infants to
facilitate mother-to-child transmission of HIV-1.
Blood 120, 43834390 (2012).
22. Dos Santos, A. B.et al.Immune cell profile in infants
lung tissue.Ann. Anat. http://dx.doi.org/10.1016/
j.aanat.2013.05.003(2013).
23. Kupper, T. S. Old and new: recent innovations invaccine biology and skin T cells.J. Invest. Dermatol.
132, 829834 (2012).
24. Sanders, M. E.et al.Human memory T lymphocytes
express increased levels of three cell adhesion
molecules (LFA-3, CD2, and LFA-1) and three other
molecules (UCHL1, CDw29, and Pgp-1) and have
enhanced IFNproduction.J. Immunol. 140,14011407 (1988).
25. Smith, S. H., Brown, M. H., Rowe, D., Callard, R. E. &
Beverley, P. C. Functional subsets of human helper-
inducer cells defined by a new monoclonal antibody,
UCHL1. Immunology 58, 6370 (1986).
26. Sallusto, F., Lenig, D., Forster, R., Lipp, M. &
Lanzavecchia, A. Two subsets of memory T
lymphocytes with distinct homing potentials and
effector functions. Nature 401, 708712 (1999).
This publication is a seminal study that describes
memory T cell heterogeneity in humans and
establishes a new paradigm for memory T cell
heterogeneity.
27. Sallusto, F., Geginat, J. & Lanzavecchia, A. Central
memory and effector memory T cell subsets: function,
generation, and maintenance.Annu. Rev. Immunol.
22, 745763 (2004).
28. Masopust, D., Vezys, V., Marzo, A. L. & Lefrancois, L.
Preferential localization of effector memory cells in
nonlymphoid tissue. Science 291, 24132417
(2001).
This study establishes the heterogeneous tissue
distribution of antiviral memory CD8+T cells, as
well as the biased distribution of TEM
cells in
non-lymphoid sites.
29. Reinhardt, R. L., Khoruts, A., Merica, R., Zell, T. &
Jenkins, M. K. Visualizing the generation of memory
CD4 T cells in the whole body. Nature 410, 101105
(2001).
30. Wang, A.et al.The stoichiometric production of IL-2
and IFNmRNA defines memory T cells that can self-renew after adoptive transfer in humans. Sci. Transl.
Med. 4,149ra120 (2012).
31. Pedron, B.et al.Development of cytomegalovirus andadenovirus-specific memory CD4 T-cell functions from
birth to adulthood. Pediatr. Res. 69, 106111 (2011).
In this study, the authors provide a comprehensive
assessment of CMV-specific and adenovirus-
specific memory T cells in a large cohort, in
cross-sectional studies of individuals from birth to
throughout adulthood.
32. Champagne, P.et al.Skewed maturation of memory
HIV-specific CD8 T lymphocytes. Nature 410,
106111 (2001).
33. Ellefsen, K.et al.Distribution and functional analysis
of memory antiviral CD8 T cell responses in HIV-1
and cytomegalovirus infections. Eur. J. Immunol. 32,
37563764 (2002).
34. Fearon, D. T., Carr, J. M., Telaranta, A., Carrasco, M. J.
& Thaventhiran, J. E. The rationale for the
IL-2-independent generation of the self-renewing
central memory CD8+T cells. Immunol. Rev. 211,
104118 (2006).
35. Gattinoni, L.et al.A human memory T cell subsetwith stem cell-like properties. Nature Med. 17,
12901297 (2011).
This study identifies a new, self-renewing
population of memory T cells in human blood,
designated TSCM
cells, and provides functional and
phenotypic characterization, as well as
enumerating their potential in immunotherapy.
36. Zhang, Y., Joe, G., Hexner, E., Zhu, J. & Emerson, S. G.
Host-reactive CD8+memory stem cells in graft-
versus-host disease. Nature Med. 11, 12991305
(2005).
37. Gattinoni, L., Ji, Y. & Restifo, N. P. Wnt/-cateninsignaling in T-cell immunity and cancer
immunotherapy. Clin. Cancer Res. 16, 46954701
(2010).
38. Gattinoni, L., Klebanoff, C. A. & Restifo, N. P. Paths to
stemness: building the ultimate antitumour T cell.
Nature Rev. Cancer. 12, 671684 (2012).
39. Klebanoff, C. A., Gattinoni, L. & Restifo, N. P.
CD8+T-cell memory in tumor immunology and
immunotherapy. Immunol. Rev. 211, 214224 (2006).
40. Lanzavecchia, A. & Sallusto, F. Progressive
differentiation and selection of the fittest in the
immune response. Nature Rev. Immunol. 2, 982987
(2002).
41. Ahmed, R., Bevan, M. J., Reiner, S. L. & Fearon, D. T.
The precursors of memory: models and controversies.
Nature Rev. Immunol. 9, 662668 (2009).
42. Buchholz, V. R.et al.Disparate individual fates
compose robust CD8+
T cell immunity. Science 340,630635 (2013).
43. Gerlach, C.et al.Heterogeneous differentiation
patterns of individual CD8+T cells. Science 340,
635639 (2013).
44. Stemberger, C.et al.A single naive CD8+T cell
precursor can develop into diverse effector and
memory subsets. Immunity 27, 985997 (2007).
45. Chang, J. T.et al.Asymmetric T lymphocyte division
in the initiation of adaptive immune responses.
Science 315, 16871691 (2007).
46. Campbell, J. J.et al.CCR7 expression and memory
T cell diversity in humans.J. Immunol. 166, 877884
(2001).
47. Turner, D. L.et al.Lung niches for the generation and
maintenance of tissue-resident memory T cells.
Mucosal Immunol. http://dx.doi.org/10.1038/
mi.2013.67(2013).
48. Herndler-Brandstetter, D.et al.Human bone marrow
hosts polyfunctional memory CD4+and CD8+T cells
with close contact to IL-15-producing cells.
J. Immunol. 186, 69656971 (2011).
49. Klonowski, K. D.et al.Dynamics of blood-borne
CD8 memory T cell migration in vivo. Immunity 20,
551562 (2004).
50. Clark, R. A.et al.Skin effector memory T cells do not
recirculate and provide immune protection in
alemtuzumab-treated CTCL patients.Sci. Transl. Med.
4,117ra117 (2012).
By examining a cohort of patients being treated
with T cell depletion therapy that reduces
peripheral T cell numbers, this study provides
evidence that TRM
cells in the human skin can
provide protection against virus infection.
51. Liu, L.et al.Epidermal injury and infection during
poxvirus immunization is crucial for the generation
of highly protective T cell-mediated immunity.
Nature Med. 16, 224227 (2010).
52. Mackay, L. K.et al.Long-lived epithelial immunity by
tissue-resident memory T (TRM
) cells in the absence of
persisting local antigen presentation. Proc. Natl Acad.
Sci. USA 109, 70377042 (2012).53. Shin, H. & Iwasaki, A. A vaccine strategy that protects
against genital herpes by establishing local memory
T cells. Nature 491, 463467 (2012).
54. Masopust, D.et al.Dynamic T cell migration program
provides resident memory within intestinal epithelium.
J. Exp. Med.207, 553564 (2010).
55. Masopust, D., Vezys, V., Wherry, E. J., Barber, D. L. &
Ahmed, R. Cutting edge: gut microenvironment
promotes differentiation of a unique memory CD8
T cell population.J. Immunol. 176, 20792083
(2006).
56. Anderson, K. G.et al.Cutting edge: intravascular
staining redefines lung CD8 T cell responses.
J. Immunol. 189, 27022706 (2012).
57. Wakim, L. M., Woodward-Davis, A. & Bevan, M. J.
Memory T cells persisting within the brain after local
infection show functional adaptations to their tissue
of residence. Proc. Natl Acad. Sci. USA 107,
1787217879 (2010).
58. Casey, K. A.et al.Antigen-independent differentiationand maintenance of effector-like resident memory
T cells in tissues.J. Immunol. 188, 48664875 (2012).
59. Masopust, D. & Picker, L. J. Hidden memories:
frontline memory T cells and early pathogen
interception.J. Immunol. 188, 58115817 (2012).
60. Gebhardt, T. & Mackay, L. K. Local immunity by tissue-
resident CD8+memory T cells. Front. Immunol. 3,
340 (2012).
61. Jiang, X.et al.Skin infection generates non-migratory
memory CD8+TRM
cells providing global skin
immunity. Nature 483, 227231 (2012).
This study shows that, in mice, skin TRM
cells do not
circulate and that these cells mediate protection to
viral infection of the skin.
62. Gebhardt, T.et al.Memory T cells in nonlymphoid
tissue that provide enhanced local immunity during
infection with herpes simplex virus. Nature Immunol.
10, 524530 (2009).
REVIEWS
NATURE REVIEWS |IMMUNOLOGY VOLUME 14 | JANUARY 2014 |33
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8/12/2019 Human Memory T Cell Formation
11/12
63. Wakim, L. M., Gebhardt, T., Heath, W. R. &
Carbone, F. R. Cutting edge: local recall responses
by memory T cells newly recruited to peripheral
nonlymphoid tissues.J. Immunol. 181, 58375841
(2008).
64. Tokoyoda, K.et al.Professional memory CD4+T
lymphocytes preferentially reside and rest in the
bone marrow. Immunity 30, 721730 (2009).
65. Lugli, E.et al.Superior T memory stem cell
persistence supports long-lived T cell memory.
J. Clin. Invest.123, 594599 (2013).
66. Gebhardt, T., Mueller, S. N., Heath, W. R. &Carbone, F. R. Peripheral tissue surveillance and
residency by memory T cells. Trends Immunol. 34,
2732 (2013).
67. Clark, R. A. Skin-resident T cells: the ups and downs of
on site immunity.J. Invest. Dermatol. 130, 362370
(2010).
68. Homey, B.et al.CCL27CCR10 interactions regulate
T cell-mediated skin inflammation. Nature Med. 8,
157165 (2002).
69. Kunkel, E. J.et al.Lymphocyte CC-chemokine receptor
9 and epithelial thymus-expressed chemokine (TECK)
expression distinguish the small intestinal immune
compartment: Epithelial expression of tissue-specific
chemokines as an organizing principle in regional
immunity.J. Exp. Med.192, 761768 (2000).
70. Agace, W. W. T-cell recruitment to the intestinal
mucosa. Trends Immunol. 29, 514522 (2008).
71. Ruane, D.et al.Lung dendritic cells induce migration
of protective T cells to the gastrointestinal tract.
J. Exp. Med. 210, 18711888 (2013).
72. Edele, F.et al.Cutting edge: instructive role of
peripheral tissue cells in the imprinting of T cell homing
receptor patterns.J. Immunol.181, 37453749
(2008).
73. Stagg, A. J., Kamm, M. A. & Knight, S. C. Intestinal
dendritic cells increase T cell expression of 47integrin. Eur. J. Immunol. 32, 14451454 (2002).
74. Cimbro, R.et al.IL-7 induces expression and
activation of integrin 47 promoting naive T-cellhoming to the intestinal mucosa. Blood 120,
26102619 (2012).
75. Zhang, H. H.et al.CCR2 identifies a stable population
of human effector memory CD4+T cells equipped for
rapid recall response.J. Immunol. 185, 66466663
(2010).
76. Kim, C. H.et al.Rules of chemokine receptor
association with T cell polarization in vivo. J. Clin. Invest.
108, 13311339 (2001).
77. Campbell, D. J., Kim, C. H. & Butcher, E. C.
Chemokines in the systemic organization of immunity.
Immunol. Rev. 195, 5871 (2003).78. Andrew, D. P.et al.CC chemokine receptor 4
expression defines a major subset of circulating
nonintestinal memory T cells of both TH1 and T
H2
potential.J. Immunol. 166, 103111 (2001).
79. Seder, R. A., Darrah, P. A. & Roederer, M. T-cell quality
in memory and protection: implications for vaccine
design. Nature Rev. Immunol. 8, 247258 (2008).
80. Zhang, X.et al.Human bone marrow: a reservoir for
enhanced effector memory CD8+T cells with potent
recall function.J. Immunol. 177, 67306737 (2006).
81. Singh, S. P., Zhang, H. H., Foley, J. F., Hedrick, M. N. &
Farber, J. M. Human T cells that are able to produce
IL-17 express the chemokine receptor CCR6.
J. Immunol. 180, 214221 (2008).
This study shows how IL-17-producing human
memory T cells are specifically maintained within a
CCR6-expressing T cell subset.
82. Wan, Q.et al.Cytokine signals through PI-3 kinase
pathway modulate TH17 cytokine production by
CCR6+human memory T cells.J. Exp. Med.208,18751887 (2011).
83. Cosmi, L.et al.Human interleukin 17-producing cells
originate from a CD161+CD4+T cell precursor.
J. Exp. Med. 205, 19031916 (2008).
This study identifies a specific subset of
IL-17-producing memory T cells that expresses
CD161 in inflamed tissues.
84. Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. &
Sallusto, F. Production of interleukin 22 but not
interleukin 17 by a subset of human skin-homing
memory T cells. Nature Immunol. 10, 857863
(2009).
85. Eyerich, S.et al.TH22 cells represent a distinct human
T cell subset involved in epidermal immunity and
remodeling.J. Clin. Invest.119, 35733585 (2009).
86. Murali-Krishna, K.et al.Counting antigen-specific
CD8 T cells: a reevaluation of bystander activation
during viral infection. Immunity 8, 177187 (1998).
87. Chomont, N., DaFonseca, S., Vandergeeten, C.,
Ancuta, P. & Sekaly, R. P. Maintenance of CD4+T-cell
memory and HIV persistence: keeping memory,
keeping HIV. Curr. Opin. HIV AIDS 6, 3036 (2011).
88. Chomont, N.et al.HIV reservoir size and persistence
are driven by T cell survival and homeostatic
proliferation. Nature Med. 15, 893900 (2009).
89. Eisele, E. & Siliciano, R. F. Redefining the viral
reservoirs that prevent HIV-1 eradication. Immunity
37, 377388 (2012).
90. Chakrabarti, L. A. & Simon, V. Immune mechanisms of
HIV control. Curr. Opin. Immunol. 22, 488496(2010).
91. Youngblood, B., Wherry, E. J. & Ahmed, R. Acquired
transcriptional programming in functional and
exhausted virus-specific CD8 T cells. Curr. Opin. HIV
AIDS 7, 5057 (2012).
92. Walker, B. & McMichael, A. The T-cell response to HIV.
Cold Spring Harb Perspect Med.http://dx.doi.
org/10.1101/cshperspect.a007054(2012).
93. Marchant, A.et al.Mature CD8+T lymphocyte
response to viral infection during fetal life.J. Clin.
Invest. 111, 17471755 (2003).
94. Komatsu, H.et al.Large scale analysis of pediatric
antiviral CD8+T cell populations reveals sustained,
functional and mature responses. Immun. Ageing 3,
11 (2006).
95. He, X. S.et al.Cellular immune responses in children
and adults receiving inactivated or live attenuated
influenza vaccines.J. Virol. 80, 1175611766 (2006).
96. He, X. S.et al.Analysis of the frequencies and of the
memory T cell phenotypes of human CD8+T cells
specific for influenza A viruses.J. Infect. Dis. 187,
10751084 (2003).
97. Amyes, E.et al.Characterization of the CD4+T cell
response to EpsteinBarr virus during primary and
persistent infection.J. Exp. Med. 198, 903911
(2003).
98. Callan, M. F.et al.CD8+T-cell selection, function,
and death in the primary immune response in vivo.
J. Clin. Invest.106, 12511261 (2000).
99. Hillaire, M. L.et al.Characterization of the human
CD8+T cell response following infection with 2009
pandemic influenza H1N1 virus.J. Virol. 85,
1205712061 (2011).
100. Miller, J. D.et al.Human effector and memory CD8+
T cell responses to smallpox and yellow fever vaccines.
Immunity 28, 710722 (2008).
This study shows the generation of virus-specific
effector and memory CD8+T cell responses in the
peripheral blood at sequential time points in
humans following yellow fever vaccination.
101. Jaimes, M. C.et al.Frequencies of virus-specific CD4+and CD8+T lymphocytes secreting -interferon afteracute natural rotavirus infection in children and
adults.J. Virol. 76, 47414749 (2002).
102. Bont, L.et al.Natural reinfection with respiratory
syncytial virus does not boost virus-specific T-cell
immunity. Pediatr. Res. 52, 363367 (2002).
103. de Waal, L.et al.Moderate local and systemic
respiratory syncytial virus-specific T-cell responses
upon mild or subclinical RSV infection.J. Med. Virol.
70, 309318 (2003).
104. Gonzalez, P. A.et al.Respiratory syncytial virus
impairs T cell activation by preventing synapse
assembly with dendritic cells. Proc. Natl Acad. Sci.
USA 105, 1499915004 (2008).
105. Reed, J. R.et al.Telomere erosion in memory T cells
induced by telomerase inhibition at the site of
antigenic challenge in vivo. J. Exp. Med. 199,
14331443 (2004).
106. Vukmanovic-Stejic, M.et al.Varicella zoster-specific
CD4+Foxp3+T cells accumulate after cutaneousantigen challenge in humans.J. Immunol. 190,
977986 (2013).
107. de Bree, G. J.et al.Characterization of CD4+memory
T cell responses directed against common respiratory
pathogens in peripheral blood and lung.J. Infect. Dis.
195, 17181725 (2007).
108. de Bree, G. J.et al.Selective accumulation of
differentiated CD8+T cells specific for respiratory
viruses in the human lung.J. Exp. Med. 202,
14331442 (2005).
This report describes the initial finding of biased
distribution of memory T cells that are specific for
a lung pathogen in the lungs compared with in the
peripheral blood.
109. Piet, B.et al.CD8+T cells with an intraepithelial
phenotype upregulate cytotoxic function upon
influenza infection in human lung.J. Clin. Invest.
(2011).
110. Zhu, J.et al.Virus-specific CD8+T cells accumulate
near sensory nerve endings in genital skin during
subclinical HSV-2 reactivation.J. Exp. Med. 204,
595603 (2007).
111. Molberg, O.et al.CD4+T cells with specific
reactivity against astrovirus isolated from normal
human small intestine. Gastroenterology. 114,
115122 (1998).
112. Sewell, A. K. Why must T cells be cross-reactive?
Nature Rev. Immunol. 12, 669677 (2012).
113. Lee, L. Y.et al.Memory T cells established by
seasonal human influenza A infection cross-reactwith avian influenza A (H5N1) in healthy individuals.
J. Clin. Invest.118, 34783490 (2008).
114. Roti, M.et al.Healthy human subjects have CD4+
T cells directed against H5N1 influenza virus.
J. Immunol. 180, 17581768 (2008).
References 113 and 114 show that there is
cross-reactivity in memory CD4+T cells and
identifies pre-existing memory T cells that are
specific for avian influenza virus in individuals who
never were exposed to this virus.
115. Su, L. F., Kidd, B. A., Han, A., Kotzin, J. J. &
Davis, M. M. Virus-specific CD4+memory-phenotype
T cells are abundant in unexposed adults. Immunity
38, 373383 (2013).
This article shows cross-reactivity of virus-specific
memory T cells using tetramer enrichment and
identifies HIV-specific memory T cells in individuals
who were never infected with this virus.
116. DOrsogna, L. J., Roelen, D. L., Doxiadis, I. I. &
Claas, F. H. Alloreactivity from human viral specific
memory T-cells. Transpl. Immunol. 23, 149155
(2010).
117. Wucherpfennig, K. W. T cell receptor crossreactivity as
a general property of T cell recognition. Mol. Immunol.
40, 10091017 (2004).
118. Burrows, S. R., Khanna, R., Burrows, J. M. &
Moss, D. J. An alloresponse in humans is dominated
by cytotoxic T lymphocytes (CTL) cross-reactive with
a single EpsteinBarr virus CTL epitope: implications
for graft-versus-host disease.J. Exp. Med.179,
11551161 (1994).
119. Wucherpfennig, K. W. & Strominger, J. L. Molecular
mimicry in T cell-mediated autoimmunity: viral
peptides activate human T cell clones specific for
myelin basic protein. Cell 80, 695705 (1995).
120. Welsh, R. M. & Selin, L. K. No one is naive: the
significance of heterologous T-cell immunity.
Nature Rev. Immunol. 2, 417426 (2002).
121. Clute, S. C.et al.Cross-reactive influenza virus-specific
CD8+T cells contribute to lymphoproliferation in
EpsteinBarr virus-associated infectiousmononucleosis.J. Clin. Invest. 115, 36023612
(2005).
122. Maynard, C. L., Elson, C. O., Hatton, R. D. &
Weaver, C. T. Reciprocal interactions of the intestinal
microbiota and immune system. Nature 489,
231241 (2012).
123. Duchmann, R.et al.T cell specificity and cross
reactivity towards enterobacteria, Bacteroides,
Bifidobacterium , and antigens from resident intestinal
flora in humans. Gut 44, 812818 (1999).
124. Hand, T. W.et al.Acute gastrointestinal infection
induces long-lived microbiota-specific T cell responses.
Science 337, 15531556 (2012).
125. Hammarlund, E.et al.Duration of antiviral immunity
after smallpox vaccination. Nature Med. 9,
11311137 (2003).
This study provides direct evidence that human
memory T cells that are generated through
vaccination are long-lived without repeat antigen
exposures.126. Surh, C. D. & Sprent, J. Homeostasis of naive and
memory T cells. Immunity 29, 848862 (2008).
127. Bushar, N. D., Corbo, E., Schmidt, M., Maltzman, J. S.
& Farber, D. L. Ablation of SLP-76 signaling after
T cell priming generates memory CD4 T cells impaired
in steady-state and cytokine-driven homeostasis.
Proc. Natl Acad. Sci. USA 107, 827831 (2010).
128. Kassiotis, G., Garcia, S., Simpson, E. & Stockinger, B.
Impairment of immunological memory in the
absence of MHC despite survival of memory T cells.
Nature Immunol. 3, 244250 (2002).
129. Kassiotis, G., Gray, D., Kiafard, Z., Zwirner, J. &
Stockinger, B. Functional specialization of memory
THcells revealed by expression of integrin CD49b.
J. Immunol. 177, 968975 (2006).
130. Macallan, D. C.et al.Measurement and modeling
of human T cell kinetics. Eur. J. Immunol. 33,
23162326 (2003).
REVIEWS
34 | JANUARY 2014 |VOLUME 14 www.nature.com/reviews/immunol
2014 Macmillan Publishers Limited. All rights reserved
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8/12/2019 Human Memory T Cell Formation
12/12
131. Macallan, D. C.et al.Rapid turnover of effector-
memory CD4+T cells in healthy humans.J. Exp. Med.
200, 255260 (2004).
132. De Boer, R. J. & Perelson, A. S. Quantifying
T lymphocyte turnover.J. Theor. Biol.327, 4587
(2013).
This article contains an interesting mathematical
analysis of human T cell proliferation studies.
133. Vukmanovic-Stejic, M.et al.Human CD4+CD25hi
Foxp3+regulatory T cells are derived by rapid
turnover of memory populations in vivo. J. Clin. Invest.
116, 24232433 (2006).134. Weng, N. P., Levine, B. L., June, C. H. & Hodes, R. J.
Human naive and memory T lymphocytes differ in
telomeric length and replicative potential. Proc. Natl
Acad. Sci. USA 92, 1109111094 (1995).
135. Weng, N. P., Araki, Y. & Subedi, K. The molecular
basis of the memory T cell response: differential gene
expression and its epigenetic regulation. Nature Rev.
Immunol. 12, 306315 (2012).
136. Miconnet, I. Probing the T-cell receptor repertoire with
deep sequencing. Curr. Opin. HIV AIDS. 7, 6470 (2012).
137. Youngblood, B., Davis, C. W. & Ahmed, R. Making
memories that last a lifetime: heritable functions of
self-renewing memory CD8 T cells. Int. Immunol. 22,
797803 (2010).
138. Robins, H. S.et al.Comprehensive assessment of
T-cell receptor -chain diversity in T cells. Blood114, 40994107 (2009).
139. Robins, H. S.et al.Overlap and effective size of the
human CD8+T cell receptor repertoire.Sci. Transl.
Med. 2,47ra64 (2010).
140. Siegel, A. M.et al.A critical role for STAT3
transcription factor signaling in the development and
maintenance of human T cell memory. Immunity 35,
806818 (2011).
141. Zinkernagel, R. M. Immunological memory not
equal protective immunity. Cell. Mol. Life Sci. 69,
16351640 (2012).
142. Wilkinson, T. M.et al.Preexisting influenza-specific
CD4+T cells correlate with disease protection against
influenza challenge in humans. Nature Med. 18,
274280 (2012).
The authors of this paper carried out a livechallenge study using the influenza virus in human
subjects and establish that reduced illness
correlates with the quantity of circulating influenza
virus-specific memory CD4+T cells.
143. Lumsden, J. M.et al.Protective immunity induced
with the RTS,S/AS vaccine is associated with IL-2 and
TNF-producing effector and central memory CD4T cells. PLoS ONE. 6, e20775 (2011).
144. Hansen, S. G.et al.Cytomegalovirus vectors violate
CD8+T cell epitope recognition paradigms. Science
340, 1237874 (2013).
This study shows that vaccination with CMV-based
vectors expressing an HIV Gag protein generates
robust effector-memory CD8+T cell responses that
have a remarkably broad specificity to epitopes
presented by MHC class I and class II molecules in
a non-human primate model.
145. Hansen, S. G.et al.Profound early control of highly
pathogenic SIV by an effector memory T-cell vaccine.
Nature 473, 523527 (2011).
146. Hansen, S. G.et al.Immune clearance of highly
pathogenic SIV infection. Nature502, 100104
(2013).
147. Sallusto, F., Lanzavecchia, A., Araki, K. & Ahmed, R.
From vaccines to memory and back. Immunity 33,
451463 (2010).
148. Altman, J. D.et al.Phenotypic analysis of antigen-
specific T lymphocytes. Science 274, 9496
(1996).
149. Bakker, A. H. & Schumacher, T. N. MHC multimer
technology: current status and future prospects.
Curr. Opin. Immunol. 17, 428433 (2005).150. Tan, L. C.et al.A