Multiple roles for CD4+ T cells in anti-tumor immune responses
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Transcript of Multiple roles for CD4+ T cells in anti-tumor immune responses
Multiple roles for CD41 T cells inanti-tumor immune responses
Summary: Our understanding of the importance of CD41 T cells inorchestrating immune responses has grown dramatically over the pastdecade. This lymphocyte family consists of diverse subsets ranging frominterferon-g (IFN-g)-producing T-helper 1 (Th1) cells to transforminggrowth factor-b (TGF-b)-secreting T-regulatory cells, which have oppositeroles in modulating immune responses to pathogens, tumor cells, andself-antigens. This review briefly addresses the various T-cell subsetswithin the CD41 T-cell family and discusses recent research efforts aimedat elucidating the nature of the ‘T-cell help’ that has been shown to beessential for optimal immune function. Particular attention is paid to therole of Th cells in tumor immunotherapy. We review some of our ownwork in the field describing how CD41 Th cells can enhance anti-tumorcytotoxic T-lymphocyte (CTL) responses by enhancing clonal expansion atthe tumor site, preventing activation-induced cell death and functioning asantigen-presenting cells for CTLs to preferentially generate immunememory cells. These unconventional roles for Th lymphocytes, whichrequire direct cell-to-cell communication with CTLs, are clear examples ofhow versatile these immunoregulatory cells are.
Keywords: CD41 T lymphocyte, T-helper cells, tumor immunotherapy, cancer vaccines
CD41 T lymphocytes come in many colors and flavors
The CD4 cell surface marker has come to be associated with a
varied group of lymphocytes that orchestrate both innate and
adaptive immune responses to pathogens and tumors through
a variety of mechanisms. The prototypic member of this group
is the CD41 T-helper (Th) lymphocyte subset, which augments
both humoral and cellular immune responses (1, 2). Th cells
recognize antigen as peptide epitopes of approximately 12–20
residues long, presented by major histocompatibility complex
class II (MHC-II) molecules typically found on specialized
antigen-presenting cells (APCs) such as dendritic cells (DCs),
macrophages, and B cells (3). In some instances, Th cells can
directly recognize antigen on MHC-II-expressing tumor cells,
resulting in the production of lymphokines that hinder tumor
growth or inducing tumor cell death (4–6).
Naive CD41 Th lymphocytes develop in the thymus
following a controlled developmental path involving both
positive and negative selection to cull potentially autoreactive
cells from the repertoire while maintaining the ability to
Richard Kennedy
Esteban Celis
Immunological Reviews 2008
Vol. 222: 129–144
Printed in Singapore. All rights reserved
r 2008 The Authors
Journal compilation r 2008 Blackwell Munksgaard
Immunological Reviews0105-2896
Authors’ address
Richard Kennedy1, Esteban Celis2
1Mayo Vaccine Research Group, Mayo Clinic College of
Medicine, Rochester, MN, USA.2Immunology Program, H. Lee Moffitt Cancer Center &
Research institute, University of South Florida, Tampa, FL,
USA.
Correspondence to:
Esteban Celis
H. Lee Moffitt Cancer Center & Research Institute
University of South Florida
12902 Magnolia Drive, SRB-2
Tampa, FL 33612, USA
Tel.: 813 745 1925
Fax: 813 979 7262
e-mail: [email protected]
Acknowledgements
This work was supported in part by NIH grants
P50CA91956, R01CA80782 and R01CA103921
(to E. Celis).
129
recognize a broad range of pathogen-associated peptides
presented by self MHC-II molecules. During an immune
response, recognition of the cognate antigen presented on the
surface of an APC by the T-cell receptor for antigen (TCR)
(Signal 1) along with interaction between appropriate
costimulatory molecules such as the CD28 co-receptor with
CD80/CD86 (Signal 2) initiates activation of the naive CD41 T
cell. These activated T cells undergo a phase of robust clonal
expansion and differentiation into either effector or memory
cells. CD41 memory Th cells can be classified into two main
groups based on cell surface markers and functional capacities.
Central memory Th cells (ThCM) express high levels of CCR7
and CD62L, lack CD45RA, and traffic through the lymphoid
organs (7–9). Effector memory T cells (ThEM) are CCR7
negative and reside mostly in the blood, spleen, and in
non-lymphoid tissues (10). Long-term survival of memory Th
cells relies on the participation of costimulatory molecules
(OX40/OX40L) and the availability cytokines such as
interleukin-7 (IL-7) (11–13).
The fate and function of the activated Th cells depends in
large part upon the microenvironment present at the time of
the initial antigen encounter. The composition of the local
cytokine milieu will bias development toward one of several
alternative differentiation pathways. Likewise, the nature of the
antigen acquired by DCs will affect the expression of different
sets of costimulatory molecules, which will also dictate the
developmental path of the antigen-stimulated Th cells (14).
This additional polarizing costimulation has been termed
‘Signal 3’ and is initiated by various innate pathogen-
associated molecular pattern receptors triggered by the
various antigens (15–18). For example, DC exposure to
intracellular pathogens programs these APCs to promote
Th1-type responses, whereas exposure to helminthes drives
DCs to promote Th2 development. A similar situation may exist
for the other various regulatory subsets of Th cells (19).
CD41 T lymphocytes can be grouped into different functional
subsets based on function and cytokine secretion patterns (Fig.
1). Originally, CD41 T cells were simply classified as Type 1
effector Th cells (Th1) that produce high levels of interferon-g(IFN-g) and tumor necrosis factor-a (TNF-a) upon antigen
stimulation and being responsible for regulating delayed type
hypersensitivity (DTH) reactions and cell-mediated immunity to
intracellular pathogens and tumor cells. The Th1 developmental
pathway is driven by IL-12 activation of signal transducer and
activator of transcription 4 (Stat4) and T-bet during immune
activation of naive T cells (20). Alternatively, Th2 are
characterized by the production IL-4, IL-5, and IL-13 and are
responsible for coordinating humoral immunity, eosinophilic
inflammation, and controlling helminthic infections. IL-4 is
primarily accountable for the differentiation of Th2 cells
through Stat6 and GATA (21). The Th1 and Th2 developmental
pathways are controlled by a delicate balance of positive
feedback loops, as IFN-g enhances further Th1 development
and IL-4 supports continued Th2 differentiation. At the same
time, cross-regulation by IFN-g and IL-4 suppresses Th2 and
Th1 differentiation, respectively.
In addition to Th1 and Th2 cells, several other subsets of
CD41 T cells participate in the development of immune
responses. In many instances, these cells act to control/
suppress immune responses and play an important role in the
prevention of autoimmune diseases. The best-studied group is
the naturally occurring CD41CD251 T-regulatory cells (Tregs)
(22–24). Approximately 5–6% of the CD41 T cells exiting
from the thymus express high levels of CD25, glucocorticoid-
induced TNF receptor (GITR), and the transcription factor
forkhead box protein 3 (Foxp3) (25–27). These Tregs mediate
Fig. 1. Diversity of CD4-expressing cell subsets. The naturally occur-ring Tregs and NKT cells both develop in an antigen-independent fashionand exit the thymus fully functional. The remaining CD41 T-cell subsetsdevelop from naive CD41 T cells after antigen-dependent T-cell activa-tion. The microenvironment present during priming, including antigendose, APC type, cytokines, and costimulatory signals, all influence thedevelopmental pathway taken by the responding T cell. The majorcytokines and secreted factors contributing to the respective functions ofthe Th subsets are listed to the right of each cell type.
130 Immunological Reviews 222/2008
Kennedy & Celis � CD41 T cells modulate tumor immunity
immune suppression through a cell-to-cell contact-dependent
mechanism that does not require antigenic stimulation (28).
While important for the prevention of autoimmunity, in some
circumstances Tregs hinder desirable immune responses, for
example against tumor-associated antigens. Depletion of this
subset in vivo, for example with anti-CD25 monoclonal
antibodies, enhances anti-tumor immunity in mice (29–32),
specially when the targeted tumor antigens are expressed to
some extent by normal cells (e.g. tissue differentiation antigens
or products of overexpressed genes). Antigen-experienced
CD41 T cells can also develop into Tregs that express CD25,
Foxp3, and GITR. Although the origins of these adaptively
induced Tregs is unclear, they have similar immune suppressive
effects as their naturally occurring counterparts. Other
populations of CD41 T cells that develop into functionally
active Tregs after antigen stimulation include Tr1 cells, which
produce large quantities of IL-10, and Th3 cells, which secrete
copious amounts of transforming growth factor-b (TGF-b)
(33). While Tr1 and Th3 cells utilize both secreted factors and
cell-to-cell contact to suppress immune responses, defining
specific markers for these CD41 T-cell subsets has been a
challenge (34).
Another subset of regulatory CD41 T cells called Th17 has
been described recently (35). The evidence suggests that Th17
cells develop independently from either Th1 or Th2 cells and
represent a distinct lineage (36). Th7 cells produce IL-17A,
IL-17F, TNF-a and IL-6 and coordinate tissue inflammation
and autoimmunity (37, 38). Th17 differentiation is thought to
require TGF-b and IL-6 (39). In addition, IL-23 (and perhaps
IL-1) serves as a growth/maintenance factor to this population.
Yet another recent addition to the regulatory CD41 T-cell
family is the ThFH subset (33). ThFH cells express CD200,
Bcl-6, CD84, and CXCR5 and migrate to the B-cell follicles after
activation (40). These cells are thought to play a role in both
antibody responses and autoimmunity; however, a definitive
function and lineage have yet to be determined (41). Last but
not least are the type-II natural killer T (NKT) cells, which
express the CD4 marker, have a limited TCR repertoire, and
recognize lipid epitopes presented by the CD1d molecule
(42–44). Type-II NKT cells secrete IL-4 and its related
cytokine IL-13, which induce myeloid derived suppressor
cells to secrete the inhibitory cytokine TGF-b. Defects in
Type-II NKT cell function result in overactive Th1 responses
and increased autoimmune pathology (45–47). In addition,
type-II NKT cells can suppress tumor immunosurveillance
through multiple mechanisms (48–50). Directed modulation
of type-II NKT cell activity is a promising avenue of increasing
tumor immunotherapy (51–53).
CD41 T cells comprise a large and growing body of distinct
cell subsets that carry out specialized immunoregulatory
functions to either enhance or inhibit immune responses. The
delicate balance of CD4-expressing lymphocytes ensures the
development of appropriate and protective immune responses
while limiting potentially damaging autoimmune disorders.
Conventional roles of Th cells in cytotoxicT-lymphocyte responses
The original concept of T-cell ‘help’ originated in the 1970s
with the description of the ‘carrier effect,’ where it was
determined that B-cell activation leading to the production of
high affinity antibody responses required two signals (54). The
first signal was provided by antigen recognition by the B cells
through cell surface immunoglobulin (Ig) receptors for antigen,
and the second signal came from interactions of the B cells
with CD41 Th cells reactive toward the same or a physically
linked (carrier) antigenic determinant. A similar helper effect
for CD81 cytotoxic T-lymphocyte (CTL) responses was
described one decade later (1). Initially thought of as primarily
cytokine producers, the role of Th cells in providing help for B
cells and CTLs is now recognized as being more complex,
involving a myriad of mechanisms. Cellular immunity against
tumors initially focused on CTLs, but in recent years it became
evident that CD41 T cells also play a critical role in the
development of effective anti-tumor immunity. Next we
describe some of the conventional mechanisms of T-cell help
that have been reported in the literature, focusing on the role of
CD41 T cells for CTL responses. In addition, we also address
some of the unconventional roles that CD41 T cells may play in
regulating CTL responses.
Before regulating anti-tumor CTL responses, both Th1 and
Th2 subsets can activate innate immune mechanisms that may
have activity against tumor cells. IFN-g production by Th1 cells
stimulates production of reactive oxygen/nitrogen species by
macrophages, which have been implicated in tumor cell
destruction. Th2 cells recruit eosinophils and stimulate
production of eosinophil cationic protein (ECP) and major
basic protein (MBP) (55). Th cells also recruit macrophages,
granulocytes, and NK cells to the tumor site (56–58). Anti-
tumor responses mediated by NK cells have also shown a
crucial need for CD41 T-cell help (59). While Th cells can have
direct anti-tumor effects through secretion of cytokines such as
TNF-a or by directly exerting tumor cell death through the
TNF-related apoptosis-inducing ligand (TRAIL) or Fas/Fas
ligand (FasL) pathways (60, 61), their major contribution for
anti-tumor effects is thought to be by providing the required
Immunological Reviews 222/2008 131
Kennedy & Celis � CD41 T cells modulate tumor immunity
T-cell help for generating and augmenting tumor-specific CTL
responses. T-cell help can be directly provided to the CTL and/
or indirectly through accessory cells (APCs, NK cells) and can
have a profound influence not only on primary CTL responses
but also CD81 memory T-cell formation.
One major form of T-cell help comes from the transient
expression of CD40L on activated Th cells, which interacts with
CD40 on the surface of DCs, activating these APCs, enhancing
the expression of both MHC and costimulatory molecules, as
well as stimulating the production of cytokines (e.g. IL-12) that
are indispensable for CTL responses (62–64). A more direct
type of help for CTLs comes in the form of cytokines such as
IL-2 that function as growth factors for CTLs. Recently the
presence of IL-2 during priming has been shown to be
essential for the secondary expansion of memory CD81 T cells
(65). IL-2 secretion by Th cells can also function to recruit and
retain CTLs at the tumor site. IFN-g production by CD41 Th1
cells results in the upregulation of MHC molecules on tumor
cells leading to enhanced T cell (CTL and Th) recognition.
Various model systems show differing requirements for
CD41 Th cells during primary CTL responses have led to
the classification of CTL responses as Th-dependent or
Th-independent responses (66–68). It is possible that strong
CTL epitopes (e.g. high MHC-binding peptides from foreign
antigens) may induce CTLs capable of producing their own
IL-2, while weak epitopes (e.g. low MHC-binding peptides
from tumor-associated antigens) will require local IL-2
production by Th cells. Other costimulatory signals may play a
role in determining whether or not primary CTL responses will
require direct T-cell help, as high levels of CD70 expression on
DCs has been shown to circumvent the need for CD41 T cells.
However, the expression of CD70 on DCs is the result of CD40
crosslinking by Th cells (69).
In addition to their role in supporting optimal primary CTL
responses, a number of studies have shown a critical need for
Th cells in the generation and maintenance of memory CD81 T
cells, a requirement which extends to both Th-dependent and
Th-independent CTL responses (67, 70–73). It has also been
shown that the CD81 T cells that acquire a memory-like
phenotype during homeostatic division are also dependent
upon the presence of CD41 Th cells (74). Other in vitro studies
have shown, under some conditions such as with the provision
of agonistic anti-CD40 antibodies or Toll-like receptor (TLR)
stimulation, that it is possible to circumvent the need for T-cell
help to generate memory CTL responses (62, 64, 69, 75, 76).
However, it is not clear what the exact role of the Th cell is in
allowing the persistence of memory CTLs once these cells have
been generated. The emerging picture is that CD41 T cells
provide conditioning signals (direct and indirect via APCs) to
naive CD81 T cells during their initial activation. Without these
signals, CD81 memory T-cell differentiation is impaired (70).
In support of this hypothesis, it has been shown that Th cells
regulate the expression of TRAIL on activated CTL. ‘Helped’
CD81 T cells are less susceptible to activation-induced cell
death (AICD) upon secondary stimulation than their ‘helpless’
counterparts (77), which may help to explain part of the role
of CD41 T cells in generating and maintaining CD81 T-cell
memory (78).
Role of Th cells during the effector phase of theimmune response
The longevity of T-cell responses during viral infections or anti-
tumor immunity is a crucial factor in determining whether a
virus or a tumor will be eliminated. Given the terminally
differentiated nature of effector CTLs and their susceptibility to
AICD and antigen-induced non-responsiveness (AINR), it
would seem that CTL responses must race against the clock to
eliminate the pathogen or tumor before natural regulatory
mechanisms curb the response and CTL clonal contraction
ensues (79–81). Typically, antigen-specific CTLs are difficult to
maintain for long periods of time, even with appropriate APCs
and growth factors such as IL-2. However, under certain
conditions in vitro, it has been possible to expand and maintain
CTLs for extended periods of time (82–84). The massive CTL
expansion (approximately 1000-fold) in tissue cultures sup-
plemented with IL-2, TCR stimulation, and feeder cells, known
as the rapid expansion method (REM), seems at odds with the
multiple regulatory mechanisms designed to check CTL expan-
sion in vivo. Notably, depletion of CD41 T cells from the feeder
cell population in the REM cultures decreased both the expan-
sion and lytic activity of the CTLs by approximately one half
(85). The CTL expanding activity of the CD41 T cells required
direct cell-to-cell contact between CTLs and Th cells and could
not be substituted simply by providing CD41 T-cell-condi-
tioned media (85). Given that CTLs and Th cells express a large
variety of costimulatory receptors and their corresponding
ligands, these molecules became attractive targets to examine
the mechanism of this effect. For example, CD28 is expressed
on most naive and early-activated T cells, while CD80 and
CD86 have been found on activated Th cells (86, 87). A similar
situation exists with several other costimulatory molecules
including the following: CD2, CD27, CD30, 4-1BB, and
cytotoxic T-lymphocyte antigen-4 (CTLA-4). Activated, human
CTLs express MHC-II, and crosslinking of this molecule on
CTLs provides a costimulatory signal to the T cell (88–91).
132 Immunological Reviews 222/2008
Kennedy & Celis � CD41 T cells modulate tumor immunity
Thus, direct interaction between MHC-II on the CTL and the Th
cell TCR could be another possible source of costimulation for
CTLs. The involvement of several molecules was first tested
using plate-bound antibodies in order to crosslink the costi-
mulatory CTL receptors, and the results showed that activation
of CD27, CD137, and MHC-II could significantly enhance the
proliferative response of CTLs to TCR stimulation (85). Further
confirmation of the role of these molecules in the Th cell-
derived proliferation signal was provided by the use of soluble
blocking antibodies to these molecules, which abrogated the
enhancement of CTL proliferation by Th cells (85). This
additional type of T-cell help may help to explain the fact that
many CTL responses are short lived and are unable to contain
chronic infections and tumor growth in the absence of Th cells
(92, 93). Although this form of T-cell help may occur in the
lymph node during the initial activation and expansion of
naive Th cells and CTLs, it is probably most effective at the
tumor or infection site between previously activated CTLs and
Th cells. One may envision the following situation: (i) antigen-
specific Th cells are stimulated at the tumor site by resident
APCs expressing tumor antigen (peptides derived from tumor
antigens presented in the context of MHC-II), alternatively the
Th cells may recognize tumor antigens presented by MHC-II-
expressing tumor cells; and (ii) the activated Th cells expressing
costimulatory molecules and secreting lymphokines would
provide local or direct growth and survival signals to the
tumor-specific CTLs, allowing them to expand and/or avoid
AICD. Thus, this type of T-cell help bolsters CTL responses
during the effector phase of the immune response, allowing it
to be better able to eliminate tumors and infectious agents.
Requirement for CD41 T cells in anti-tumorpeptide vaccines
Another line of research in our laboratory involves examining
the different roles that CD41 and CD81 T lymphocytes play in
immune responses to tumors following peptide vaccination.
One tumor model for these experiments is the B16 mouse
melanoma, a poorly immunogenic tumor, which, like many
of its human counterparts, expresses the tumor-associated
antigen tyrosinase-related protein-2 (TRP-2). The vaccination
protocol consisted of a peptide representing the CTL epitope
TRP-2188–188 administered in incomplete Freund’s adjuvant (IFA)
along with immunostimulatory CpG-containing oligodeoxy-
nucleotides (a TLR9 agonist) and anti-CTLA-4 blockade as
adjuncts. Vaccination of the mice prophylactically (before
tumor challenge) or therapeutically against the B16 melanoma
resulted in equally robust CTL responses; however, the
prophylactic vaccine had no effect on animal survival after the
lethal tumor challenge. In contrast, therapeutic administration
of the vaccine significantly delayed tumor growth, and double
vaccination (administered both before and after challenge)
resulted in significant protection against the tumors, where
80% of mice survived (94). This survival advantage conferred
by the double vaccine administration was abrogated in CD81
or CD41 T-cell deficient mice, indicating that both cell types
were required for protective immunity. While mice vaccinated
prophylactically or therapeutically exhibited CD81 T-cell
responses of similar magnitude shortly after tumor challenge,
the CTL responses steadily decreased in mice immunized
before tumor challenge, while animals vaccinated after tumor
implantation maintained high levels of CTL activity. This CTL
activity correlated with the presence of tumor-specific Th
responses in the animals. These results indicated that antigen-
specific Th cells were not necessary for the induction of the
CD81 T-cell response but in turn facilitated the persistence of
CTL effector function in the tumor-bearing mice.
The role of Th cells in maintaining CTL responses
In other studies, we utilized the B16-ovalbumin (OVA) mela-
noma line expressing OVA as a surrogate tumor-specific anti-
gen to further address the role of T-cell help in the efficacy of
peptide-based vaccines for tumor immunotherapy (95). Simi-
lar to other reports showing that CD41 T-cell help was
dispensable for primary CTL responses (67, 96, 97), we found
that peptide OVA257–263 (or SIINFEKL, the immunodominant
CTL epitope of OVA) immunization could induce robust,
protective CTL responses that were able to clear tumors in
60% of lethally challenged mice. In this model system, we
investigated the effect of supplementing the CTL peptide
vaccine with MHC-II-restricted peptides representing Th epi-
topes. In one vaccine type, we utilized a Th epitope expressed
by the tumor model antigen (OVA323–339), while in the other
vaccine type contained an irrelevant Th epitope [Pan-DR
epitope (PADRE)] that was not expressed by the tumor. While
the addition of either one of the Th peptide epitopes to the
vaccine led to greater CTL activity, only the use of Th peptide
epitope expressed by the tumor (OVA323–339) led to an
increased effect on survival. In these studies, we found that Th
cells had no direct activity against B16-OVA, nor did immuni-
zation with the Th epitopes alone have a significant effect on
either tumor growth or mouse survival. Interestingly, delaying
tumor challenge by as little as 2 weeks after vaccination
decreased survival in the group receiving CTL peptide alone
from 60% to 20%, indicating that in the absence of Th cell
Immunological Reviews 222/2008 133
Kennedy & Celis � CD41 T cells modulate tumor immunity
stimulation the CTL responses were short lived. Given the
similarities in the levels of detectable CTL of the mice from
each vaccine group and given the fact that non-specific
(irrelevant) T-cell help had no beneficial effect on survival
against the tumor, we hypothesized that tumor-specific CD41
Th cells were providing ‘help’ directly at the tumor site,
perhaps by increasing CTL survival during the effector phase
of the immune response. To test this possibility, we developed
an in vitro model to measure antigen-specific CTL AICD using
peptide/MHC monomers to activate the TCR. This model
system allowed us to test the effects that the presence of Th
cells would have on CTL AICD when previously activated CTLs
reencountered antigen. Our results clearly showed a significant
decrease in CTL death (approximately 50% reduction) in the
presence of Th cells (95). Further experimentation showed that
protection was not associated with decreased CTL activation (in
fact ‘protected’ CTLs had significantly higher lytic activity) and
that the protective effect required direct cell-to-cell contact
between Th cells and CTLs. Although the exact mechanism of
this protection remains to be determined, we observed that Th
cells and CTLs interact with each other via CD2/CD48 associa-
tions, leading to lipid raft aggregation and recruitment of the
CTL TCR into the lipid rafts, which could optimize the signals
received by the CTL through its TCR upon interaction with the
antigen-expressing tumor cell. Under normal circumstances,
CTL-target interactions lead to two signals in the CTL, one
signal to release perforin/granzymes onto the target cell and a
second signal leading to a self-death inducing stimulus. The
bottom line is that in many instances, CTLs are only able to kill
a limited number of target cells before they succumb to AICD.
Nevertheless, in the presence of Th cells, CTLs receive a
protective stimulus that increases resistance to AICD and allows
survival and continued killing. We postulate that these ‘helped’
CTLs would not only be better able to clear infection/tumor
but may also be more likely to contribute to the CD81 T-cell
memory pool (Fig. 2). Decreased CTL susceptibility to AICD
may account for the greater protection seen in our experi-
mental tumor model when mice were primed with both CTLs
and Th epitopes (95) as well as in the rapid CTL expansion
experiments (85). The anti-apoptotic effect conferred by
Th cells may also be at work in viral infections and in
autoimmunity. In some viral infections, CTLs expand and
transiently control infection, but the CTL response is eventually
lost and viremia remains uncontrolled in a chronic state. It is
possible that inappropriate Th responses could be responsible
for the lack of a robust, long-lasting CTL response needed for
the elimination of the viral infection. In the male antigen (HY)
model system, it has been shown that the survival of TCR
transgenic CD81 T cells is increased with concurrent CD41 T-
cell stimulation (98). A similar result has been observed in the
OVA system using the rat insulin promoter (RIP)-OVA mice,
which express OVA in the pancreatic islet cells (99). OVA-specific
TCR transgenic CTL (OT-1) T cells, transferred into RIP-OVA
mice in large numbers, expand, become activated, and destroy
the b pancreatic islet cells and induce diabetes. However, low
numbers of OT-1 cells expand briefly in the draining lymph
node and are subsequently deleted before islet destruction
can occur. Concurrent transfer of CD4, OVA-specific Th cells
(OT-II) reduced the number of OT-1 cells required for induc-
tion of diabetes by preventing the deletion of OT-1 cells in the
RIP-OVA animals (99). While the importance of CD41 Th cells
in CTL responses is well recognized, not many mechanisms
have been put forth to explain their dramatic effects on CTL
responses during the effector phase of the immune response.
By providing survival signals to CTLs, Th cells block AICD and
increase the expansion of CTLs and their functional lifespan. By
allowing more CTLs to escape deletion, Th cells will also
promote greater CTL memory generation.
Fig. 2. Th cell-mediated protection of CTLs from AICD. (A) Uponsecondary encounter with APCs, CTLs release cytotoxic components(perforin, granzyme B) towards the target cell and in turn receive signalsthrough death receptors (FasL, TRAIL, TNFR), which initiate apoptoticsignaling cascades within the CTL. (B) The close proximity of Th cellsallows for costimulatory signals that reduce CTL susceptibility to AICDand may also increase proliferative capacity. This protective effect may bemediated by direct anti-apoptotic signals or a qualitative change insignaling through the TCR. Protected CTLs exhibit enhanced effectorfunction.
134 Immunological Reviews 222/2008
Kennedy & Celis � CD41 T cells modulate tumor immunity
Th cells as APCs?
The interaction between Th cells and CTLs leading to increased
proliferation (85) and reduced AICD (95) requires cell-to-cell
contact and it is mediated through the binding of costimula-
tory molecules with their respective ligands and perhaps also
via Th cell-derived cytokines. One can easily envision that cell-
to-cell communication between Th cells and CTLs either in
secondary lymphoid organs or at the tumor site would be more
efficient if these cells interacted with each other in an antigen-
specific manner, for example by Th cells presenting MHC-I/
peptide complexes to the CTLs. Nevertheless, it is not so easy to
imagine how Th cells would gain access to antigens and process
them into MHC-I-binding peptides, because these cells are not
considered professional APCs. In the early 1980s, several
reports indicated that murine T cells in mixed lymphocyte
cultures acquired MHC molecules from the professional APCs
during the activation process (100–105). More recent reports
have confirmed this phenomenon and have shown that T cells
can capture cell surface proteins including MHC products from
APCs in a TCR-dependent manner (106–115). In addition to
MHC-I and II interchanges, a variety of other costimulatory
(B7.1 and B7.2) and adhesion (intercellular adhesion
molecule-1) molecules (108, 116, 117) or even extensive
membrane fragments can be acquired by the T cells (110). Most
significantly, not only are these molecules transferred to T cells
but also they are functional on the T-cell surface (106, 109, 110,
112, 114, 115, 118, 119). To study this phenomenon, our
laboratory utilized CD81 T cells from patients with bare lym-
phocyte syndrome, which lack surface expression of MHC-II due
to a mutation in the RFX5 gene. Our results show that while cell-
to-cell contact between the T cell and APC resulted in optimal
transfer of MHC-II, there was also a low level of cell surface
material transferred by exosomes shed from the APCs (120). The
transfer of MHC-II from APCs to MHC-II-deficient T cells was
mediated by various molecule pairs including CD8/MHC-I and
CD2/CD58. Interestingly, depletion of cholesterol from the
plasma membrane of the T cells resulted in a significant reduction
in the amount of acquired MHC-II, indicating that the choles-
terol-rich lipid rafts may play a vital role in the transfer
mechanism. Thus, these observations indicate that one
mechanism for Th cells to generate MHC-I/peptide complexes
to be presented to CTLs would be simply to grab them from
APCs during the antigen recognition process.
Another mechanism by which Th cells may gain access to
MHC-I-binding peptides could be when the Th cell’s TCR
interacts with MHC-II/peptide complexes, when the particular
peptide also includes an adjoining CTL epitope. Supporting this
possibility is the fact that CTLs and Th cell epitopes are frequently
found in close proximity or even overlapping one another (Table
1). In most of the cases presented in Table 1, the peptides were
found to stimulate both MHC-I and II T-cell responses in the
same individual. Furthermore, the CTL epitopes situated
within or near Th cell epitopes tend to be the strongest
immunodominant epitopes. With this information on hand, we
have proposed a model where the Th cell, while interacting with
an APC, would retain and internalize the MHC-II/peptide
complex and that somehow, through limited antigen processing
in the endosomal compartments, the CTL epitope contained
within the MHC-II-binding peptide, would be generated. The
CTL peptide epitope would bind to those MHC-I molecules that
recirculate through the early endosomal compartment.
Supporting this model, there are a number of reports showing
that MHC-I molecules recycle through the endosomal
compartment are able to efficiently pick up new peptides,
including some derived from degraded MHC-II molecules, and
carry them to the cell surface, a process that is facilitated by the
low pH (pH approximately 5.0) of the early endosomal
compartment (121–125). It has been suggested that this
exogenous loading pathway amplifies the repertoire of peptides
that can be presented by MHC-I molecules. In the case of MHC-II
epitopes that overlap or are linked with CTL epitopes, the MHC-I
binding peptide would have to be generated by proteases
residing in the endosomes. It should be noted that both the
acquired MHC-II/peptide complexes and the endogenous MHC
class I molecules are present in an environment well suited to
MHC-I peptide loading (124, 126), so it is not far fetched to
propose that the antigenic peptides contained by the acquired
peptide/MHC-II complexes can be processed and loaded onto
the recycling, endogenous MHC-I molecules and be transported
to the cell surface to become accessible for CTL presentation. In
support of this theory, it has been shown that proteins targeted to
the surface of CD41 T cells, such as antibodies or viral proteins,
are internalized, processed, and able to generate MHC-I and II-
binding peptides that find their way back onto the cell surface.
Subsequently, both MHC-I and II epitopes from these proteins
are presented by the CD41 T cells to other T lymphocytes
(127–130). This is an attractive situation from an immunologic
standpoint, as it would provide not only antigen stimulation but
also immediate T-cell help through both direct costimulation and
cytokine secretion to the CTLs.
To study some of the possible mechanisms by which MHC-I/
peptide complexes that are specific for nearby CTLs can be
generated by Th cells, we developed a model system that
allowed us to modify the MHC-I molecules on both the APC
and/or the Th cells. The multiple mechanisms of antigen
Immunological Reviews 222/2008 135
Kennedy & Celis � CD41 T cells modulate tumor immunity
acquisition described below are depicted in Fig. 3. This model
system utilized the 25.D1.16 monoclonal antibody (mAb) that
recognizes the H-2Kb/SIINFEKL complex (131) and the OT-1,
OT-II, and DO11.10 TCR transgenic mice whose T cells
recognize two OVA peptides, OVA257–263 (restricted by
H-2Kb) and OVA323–339 (restricted by I-Ab or I-Ad). The first
scenario explored the simple shedding of CTL peptide epitopes
from inside the APC or from the APC surface, which would
simply bind to cell surface MHC-I on the Th cell (Fig. 3, #1).
A second mechanism would be the above-described acquisition
of MHC-I molecules from the APC (Fig. 3, #2). For these
experiments, we used the LB27.4 cell line, which expresses
MHC-I and II from the H-2b and H-2d haplotypes, as the APCs.
CD41 Th cells specific for the OVA323–339 were obtained from
either DO11.10 (H-2d) or OT-II (H-2b). The use of antigen-
experienced, pre-activated Th cell lines showed that the Th cell
could directly pick up MHC-I/peptide complexes from the APC
and that the transfer of these molecules did not require the
presence of the Th-specific antigen (Fig. 4A). When resting
(naive) Th cells were used, antigen presentation via MHC-II/
OVA323–339 by the APC was required for MHC-I acquisition to
take place. A third mechanism involves the acquisition of MHC
I/peptide complexes from the APC followed by the transfer of
the epitope to the self (endogenous) Th MHC-I molecules (Fig.
3, #3). To distinguish between the acquired MHC-I and the
endogenous MHC-I of the Th cell, we utilized several mutants
Table 1. Proximal T-helper and CTL epitopes
Antigen
MHC-II (Th) MHC-I (CTL)
Epitope Restriction Epitope Restriction Reference
Tumor antigensCEA 653–667 HLA-DR4, 7, 9 652–660 HLA-A24 (152)HTLV-1 env 196–210 HLA-DR9 175–183 HLA-A2 (4)HTLV-1 env 196–210 HLA-DR9 182–190 HLA-A2 (4)HTLV-1 env 384–398 HLA-DR15 395–403 HLA-A2 (4)HTLV-1 tax 191–205 DR1, DR9 181–195 HLA-B14 (5)HTLV-1 tax 305–319 DR15, DQ9 301–309 HLA-A24 (5)Melanoma gp100 175–189 HLA-DR53, DQ6 177–186 HLA-A2 (152)NY-ESO-1 87–98 Promiscuous, HLA-DR7 80–88 HLA-Cw6 (153, 154)NY-ESO-1 87–98 Promiscuous, HLA-DR7 92–100 HLA-Cw3 (153, 154)NY-ESO-1 87–98 Promiscuous, HLA-DR7 84–102 HLA-B51 (153, 154)NY-ESO-1 80–109 Promiscuous, HLA-DR7 80–88 HLA-Cw6 (153, 154)NY-ESO-1 80–109 Promiscuous, HLA-DR7 92–100 HLA-Cw3 (153, 154)NY-ESO-1 80–109 Promiscuous, HLA-DR7 84–102 HLA-B51 (153, 154)P1A 33–44 I-Ad 35–43 Ld (155, 156)p53 234–242 H-2d MHC II 234–242 Kd (157)Ras oncogene 4–16 I-Ad 4–12 Kd (158, 159)WT1 124–138 HLA-DR53 126–134 HLA-A2 (6)WT1 247–261 HLA-DR53 235–243 HLA-A24 (6)
AutoantigensGAD 206–220 I-Ag7 206–214 Kd (160)GAD 509–527 I-Ag7 505–513 Kd (160)GAD 524–543 I-Ag7 546–554 Kd (160)Insulin 9–23 I-Ag7 15–23 Kd (161, 162)
Viral antigensHBV env 10–19 HLA-DQ5 10–17 HLA-A11 (163)HBV env 182–191 HLA-DPw3 183–191 HLA-A2 (163)HBV env 182–196 HLA-DR2w15, DPw4 183–191 HLA-A2 (163)HIV-1 gp160 315–327 I-Ad 318–327 Dd (164)HIV-1 RT 36–52 H-2k MHC II 38–52 H-2k (165)Influenza B NP 335–349 HLA-DQw5 335–349 HLA-B37 (166)Rubella Capsid 263–275 HLA-DR 264–272 HLA-A3, 11 (167)Vaccinia A18R 49–63 I-Ab 57–64 Kb (168, 169)
Other antigensHEL 91–105 I-Ag7 91–99 Kd (160)HEL 106–116 I-Ed 116–124 Kd (160)OVA 265–280 I-Ab 257–264 Kb (170)
The first column indicates the type of antigen and source of the defined T-cell epitopes. The location of the MHC-II epitope within the protein and itsrestriction element are listed in columns 2 and 3. Columns 4 and 5 contain the same information for the proximal or overlapping MHC-I epitopes.Column 6 contains the bibliographical reference.MHC, major histocompatibility complex.
136 Immunological Reviews 222/2008
Kennedy & Celis � CD41 T cells modulate tumor immunity
of the Kb molecule. The mutant Kbm3 also binds the OVA257–263
epitope, and this complex is also recognized by the 25.D1-16
Ab. An additional mAb, B8-24-3, binds to Kb but not Kbm3,
allowing for distinguishing Kb/OVA257–263 from Kbm3/
OVA257–263 complexes. The results showed that incubation of
activated OT-II Th cells with OVA257–263-pulsed Kbm3 APCs
resulted in the surface expression of both Kb/OVA257–263 and
Kbm3/OVA257–263 complexes on the Th cell surface. This effect
was enhanced in the presence of the Th-specific MHC-II
peptide OVA323� 339. Resting (naive) OT-II Th cells, however,
required the presence of their cognate MHC-II peptide
OVA323–339 to produce MHC-I/OVA257–263 complexes. More
importantly, the majority of the OVA257–263 on the naive Th
cells was presented in the context of the Th cell endogenous Kb,
not with the acquired Kbm3 from the APC. These results
demonstrated that not only could CD41 Th cells acquire MHC
I/peptide complexes from a nearby APC but they could also
re-present the acquired peptide on their own MHC-I molecules.
As previously mentioned, a fourth mechanism of antigen
transfer from APC to Th cells involves the presence of Th cell
epitopes that contain within their sequence CTL epitopes (Fig.
3, #4). To test this possibility, APCs loaded with linked
peptides containing both MHC-I and II epitopes were
co-incubated with antigen-specific Th cells. After a short
incubation, MHC-I/peptide complexes could be detected on
the surface of the Th cell, indicating that after recognition of
the MHC class II-peptide complex by the Th cell, the complex
was internalized, the full length peptide was processed, and the
MHC-I binding fragment was loaded onto the recirculating
MHC-I molecules (118, 119, 126) (Fig. 4B). Overall, these
experiments indicate that Th cells possess sophisticated
antigen-processing capabilities similar to other professional
APCs, such as cross-presentation. In some ways this process is
similar to B-cell internalization/processing of antigen through
the B-cell receptor for antigen (surface Ig) (132, 133).
Our work also reinforced a consistent theme: the need for Th
cell activation before the antigen acquisition can occur. This
requirement for TCR involvement would limit MHC and
antigen uptake to the CD41 T cells that are being activated in
response to a pathogen or tumor-derived antigens. It is evident
that the APC presenting MHC-II epitopes will also possess
MHC-I epitopes from said pathogen or tumor, so the require-
ment for linkage between CTL and Th cell epitopes would not
appear to be necessary. However, presentation of MHC-I/peptide
epitopes by Th cells could further facilitate the expansion of
DC-initiated CTL responses, because growth factors (IL-2)
would be directly delivered to the CTL via an immunological
synapse. In addition, as described below, presentation of
antigen by Th cells to naive CTLs may preferentially generate
specific functional subsets of CTLs. Our observations have been
validated by a report from another group that Th cells that have
acquired antigen and that MHC-I complexes from DCs can
stimulate effective protective tumor-specific CTL responses
in vivo (134).
Direct priming of CD81 T-cell memory by Th cellsfunctioning as APCs
Having demonstrated that Th cells are capable of acquiring and
presenting antigen to activate CTLs, we examined the func-
tional consequences of this phenomenon. Specifically, we first
addressed whether Th cells had the capability of stimulating
naive CTLs. In the past, presentation of antigen by T cells to
Fig. 3. Varied mechanisms of antigen acquisition by Th cells. (1) CTLpeptide is shed by APCs and binds to MHC-I on a nearby Th cell. (2) Cell-to-cell contact results in the direct transfer of APC MHC-I to the surface ofthe T cell. This may or may not require antigen recognition by the Th cell.(3) Acquired MHC-II molecules may travel to endosomes and transferantigen to endogenous Th cell MHC-I. (4) Large epitopes presented byMHC-II can contain both MHC-I and II T-cell epitopes (Table 1). The MHC-II/peptide complexes recognized by Th cells can be internalized andprocessed by in endosomal compartments. Proteolytic cleavage releasesthe CTL epitope, which then binds to endogenous recycling MHC-Imolecules also present in the endosome of Th cells.
Immunological Reviews 222/2008 137
Kennedy & Celis � CD41 T cells modulate tumor immunity
other T cells has been reported in some circumstances to lead to
T-cell activation, proliferation, and function (119, 127,
135–138), while in other cases it leads to tolerogenic or
suppressive effects (127, 139–142). In addition, CD81 T-cell
presentation of antigen to other activated CTLs results in
fratricide (143, 144). Most of the evaluations of T cells as APCs
have been done using pre-activated (antigen-experienced) T
cells as responders, since it was assumed that naive T cells
require professional APCs to initiate a response. Our initial
experiments comparing the ability of activated Th cells and DCs
to prime highly purified naive CD81 T cells showed two
surprising findings: (i) CTLs activated by either peptide-pulsed
DCs or Th cells progressed through an identical number of cell
divisions, and (ii) CTLs activated by Th cells showed signifi-
cantly greater initial expansion than those primed by DCs,
suggesting that Th cells as APCs lead to a reduced rate of AICD
(145). Cell surface phenotype analysis by flow cytometry was
performed on CTLs stimulated by the two APC populations
showed that both DC- and Th-primed CTLs expressed high
levels of the activation markers CD44, CD25, and CD69 (145).
However, while DC-primed CTLs rapidly lost CD62L expres-
sion, the CTLs primed by Th cells retained high levels of
CD62L, a marker found expressed by CD81 memory T cells.
Additionally, the CD44/CD62L-expressing CTLs also expressed
high levels of Ly6C (another memory cell marker). Thus, the
Th-primed CTLs bore a striking resemblance to the central
memory T-cell phenotype described earlier. In addition to the
phenotypic characteristics of this memory-like population of
CTLs, these cells behaved as conventional memory T cells: (i)
they demonstrated fully competent cytokine production but
had reduced cytolytic activity, (ii) they exhibited long-term
survival (4 2 months in vivo), and (iii) they possessed the
ability to mount recall responses to subsequent antigenic
challenge in vivo and in vitro. Several key characteristics of Th
and DC-primed CTLs are shown in Table 2. Although the exact
mechanism by which Th cells contribute to the establishment
of CD81 T-cell memory is not known, it has been proposed
that Th cells act through conditioning APCs, which then prime
CD81 T cells to generate an effector response and a CD81 T-cell
memory subset (62–64). Th cells may be the primary source of
IL-2, which is necessary for the generation of memory T cells,
during the priming of CTL responses (65). Additionally, it has
been suggested that the presence of CD41 T cells decreases
TRAIL expression in activated CTLs, increasing their survival
and capacity to differentiate into memory T cells (77). Here we
present yet another possible role for CD41 cells in CD81 T-cell
Fig. 4. Acquisition of MHC-I determinants by Th cells. (A) LB27.4 APCs were pulsed with OVA257� 264 and incubated with resting and activatedCD41 T cells from DO11.10 (DO11.10� B6)F1 and OT-II mice. (B) CD41 T cells from OT-II mice were cultured with and without T1 APCs(expressing I-Ab) in the presence of the indicated peptides. Surface expression of Kb/OVA257–264 complexes on the Th cells is indicated by the stainingintensity of the 25.D1.16 mAb.
138 Immunological Reviews 222/2008
Kennedy & Celis � CD41 T cells modulate tumor immunity
memory generation. We propose that Th cells can present antigen
directly to CD81 T cells and preferentially drive memory cell
formation (Fig. 5). This hypothesis provides a simple yet elegant
explanation for the required presence of CD41 T cells in the
generation of CD81 T-cell memory.
Fine-tuning CD41 T-cell responses in cancer vaccines togenerate effective CTL responses
The work done by our group and others has clearly shown that
CD41 T-cell responses are an important element of effective
vaccines for cancer or infectious agents. The provision of T-cell
help not only boosts CTL priming efficiency, it also serves to
program CD81 T-cell memory responses and allows the
persistence of these secondary responses and is therefore a
critical component of protective immunity. In addition to the
positive influence Th cells can have on developing immune
responses, the participation of CD4/CD25 Tregs can lead to the
opposite effect. Several studies have shown that the removal of
Tregs before vaccination is advantageous (146–148). Likewise,
the presence of Treg cells within tumors correlates with
reduced survival (149). We have tested the efficacy of tumor-
specific peptide vaccines administered with TLR ligands using
the BALB-neuT mouse tumor model. These animals express the
activated form of the rat neu oncogene (RNEU) and sponta-
neously develop breast tumors at 4–5 months of age (150).
Vaccination of wildtype BALB/c mice (parental strain of BALB-
neuT but not expressing RNEU) with a RNEU CTL peptide and
TLR9-L (CpG) induced strong CTL responses, which recognize
RNEU-expressing tumor cell lines. These tumor-specific CD81
T cells were sufficient to protect BALB/c mice from trans-
planted RNEU-expressing tumors but do not protect the BALB-
neuT mice (151). This lack of protection in the BALB-neuT
mice was due to immune tolerance, as the mice express RNEU
in breast tissues at 5–6 weeks of age. Nevertheless, when the
BALB-neuT mice were pretreated with antibodies to CD4 or
CD25 to deplete Treg cells, the magnitude of the CTL responses
Table 2. CTL characteristics after priming by professional and T-helper APCs
DC APC T-helper APC
Proliferative capacity
CFSE celldivision�
Phenotypew
CD251 95% 94%CD441 93% 97%CD62L1 11% 72%CD691 93% 62%
Effector functionCytolytic
activityz23.4% 6.0%
IFN-gproduction‰
89.2% 82.4%
Significant differences between the two CTL subsets are indicated in bold text.�CTLs were stained with CFSE before in vitro culture with peptide-pulsedAPCs (DCs or Th cells). The filled histograms represent the dividing CTLs inthe presence of the indicated antigen-pulsed APCs. The open histogramsare the same cells, incubated with APCs in the absence of antigen.wNumbers represent the % of CTLs expressing the listed surface marker72 h after priming by the indicated APC.zDC- or Th-primed CTLs were incubated with radiolabeled, antigen-expressing tumor cells. The number listed is the % specific killing at aneffector:target ratio of 30:1.‰The numbers indicate the % of DC- or Th-primed CTLs producing IFN-gafter restimulation with antigen-expressing tumor cells, as measured byintracellular staining flow cytometry.APC, antigen-presenting cells; CTL, cytotoxic T lymphocyte; IFN, interferon.
Fig. 5. Model of CD81 T-cell memory development. In this model, theeventual fate of a naive CD81 T cell depends upon the nature of the antigenpresentation. Certain factors such as high antigen density, high levels of B7,prolonged antigen presentation by professional APCs, and IL-2 predisposeto the development of effector and effector memory type T cells, whilelower antigen densities, shorter duration of antigen presentation or antigenpresentation by non-professional APCs, non-B7-mediated costimulation(4-1BB, OX-40, CD70), and the presence of cytokines such as IL-15 andTGF-b will skew development towards the central memory phenotype.Several surface molecules have been proposed as markers for effector andmemory T-cell subsets and are listed in the phenotype panel. The ‘function’panel at the bottom of the figure shows the reported effector functionalityand proliferative capacity of the various T-cell subsets.
Immunological Reviews 222/2008 139
Kennedy & Celis � CD41 T cells modulate tumor immunity
increased fivefold, with an accompanying increase in cytolytic
activity against RNEU-expressing tumor lines (151). Impor-
tantly, depletion of Treg cells using anti-CD25 mAb signifi-
cantly increased anti-tumor effects in the BALB-neuT mice to
transplanted tumors. However, administration of anti-CD4
mAb to deplete Treg cells, although previously shown to
increase CTL induction, resulted in decreased protection. These
results were likely due to the concurrent depletion of conven-
tional CD41 Th cells, which, as discussed previously, are
critical for the persistence of CTLs. The effect of peptide
vaccination on the outgrowth of spontaneously developing
tumors was also analyzed. Immunization with CTL peptide and
CpG alone could only delay tumor growth and prolonged
survival by approximately 5 weeks (151). In contrast, animals
pretreated with anti-CD25 mAb, to deplete Treg cells before
vaccination, remained tumor free 15–20 weeks after the
control animals had succumbed. These results further reinforce
the concept that CD41 T-cell responses need to be carefully
manipulated to generate the optimal effect of cancer vaccines,
allowing the development of tumor-specific T-cell help while
eliminating the detrimental pressures that Tregs exert during
immune priming.
Final thoughts
Immune responses are a result of complex interactions
between the cells of the immune system. At the heart of most
immune responses are CD41 T lymphocytes. Early studies of
these T cells showed their important role in supplying help,
mostly in the form of cytokines to other lymphocytes (B cells,
CTLs) for the generation of antibodies and mature killer cells,
hence their original name, T-helper cells. It is clear now that
lymphocytes expressing the CD4 marker belong to a large
family of cells that have one function in common: the regula-
tion and fine tuning, either upwards or downwards, of
immune responses. The function of CD41 T cells in either
enhancing or suppressing immune responses is not only
through the action of lymphokines that either stimulate or
inhibit the function of other lymphocytes but also through
cell-to-cell interactions leading to costimulation, direct inhibi-
tion, and sometimes antigen presentation. It is clear that
further research into these and other potential mechanisms of
T-cell immunoregulation will be necessary to develop vaccine
strategies to induce robust primary and optimal memory
responses that will ultimately benefit cancer patients.
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