Immunology

1

A selection of interesting papers that were published inthe two months before our press date in major journalsmost likely to report significant results in immunology.

• of special interest•• of outstanding interest

Current Opinion in Immunology 2002, 14:1–10

Selected by Tim ElliottUniversity of Southampton, Southampton, UK

e-mail: [email protected]

• C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosisand uptake of apoptotic cells. Ogden CA, deCathelineau A,Hoffmann PR, Bratton D, Ghebrehiwet B, Fadok VA,Henson PM: J Exp Med 2001, 194:781-795.Significance: The uptake of apoptotic cells by a variety of celltypes is essential for tissue homeostasis and also (when takenup by dendritic cells) for immunological regulation. This paperprovides a mechanism for this process and suggests an expla-nation for the observed correlation between C1q deficiency,abnormal clearance of apoptotic bodies and increased risk ofbacterial infections and autoimmune diseases such as SLE.Findings: C1q and its orthologue, mannose binding lectin(MBL), bound via their globular-head domains to blebs onT cells that were undergoing UV-light-induced apoptosis.C1q-coated blebs were phagocytosed by human monocyte-derived macrophages (HMDM) more effectively althoughsignificant internalisation also occurred in the absence of coating. Uptake of C1q-coated erythrocytes was blocked byantibodies to calreticulin or by C1q collagen-like tails (CT) indi-cating that C1q binds to calreticulin on the surface of HMDM viaits CT. Calreticulin was found at the cell surface of HMDM inassociation with the α-2 macroglobulin (α2m) receptor CD91and α2m reduced the efficiency of internalisation in this system.

• Defective antigen processing in GILT-free mice. Maric M,Arunachalam B, Phan UT, Dong C, Garrett WS, Cannon KS,

Alfonso C, Karlsson L, Flavell RA, Cresswell P: Science 2001,294:1361-1365.Significance: The processing of endocytosed proteins for presentation to MHC class II restricted T cells involves proteinunfolding, reduction of intramolecular disulphide bonds andproteolysis. The recently discovered γ-interferon-inducible lysosomal thiol reductase (GILT) is shown here to be essentialfor the second of these events for the in vivo processing of epitopes derived from protein antigens with intramoleculardisulphide bonds. It may therefore be a target for immunomod-ulation and, as Colin Watts points out in an accompanyingcommentary to this article, may be an important enzyme inpotentiating the toxicity of certain plant-derived and commercialdisulphide-bonded immunotoxins.Findings: A mouse with a homozygous deletion of six out ofseven of the GILT exons was generated and shown to have normal numbers of CD4+ cells in thymus and spleen. Its CD4+

T cell response to hen egg lysosyme (HEL) and Rnase A (eachwith four intramolecular disulphides), and human IgG (with mul-tiple disulphides) was decreased by 90%, whereas theresponse to the non-disulphide-bonded antigen α-casein wasbarely impaired. GILT−/− splenocytes could only generate andpresent two out of four HEL-derived epitopes to T-cell hybrido-mas, and this defect did not correlate with the presence ofcysteines in the epitopes themselves. However, the inability toprocess the remaining two epitopes was due to a lack ofGILT-catalysed reduction of HEL, since prior reduction of theantigen overcame the block in antigen processing.

• The structure of calnexin, an ER chaperone involved inquality control of protein folding. Schrag JD, Bergeron JJ,Li Y, Borisova S, Hahn M, Thomas DY, Cygler M: Molec Cell2001, 8:633-644.Significance: The lectin-like chaperones calnexin and its orthologue, calreticulin, are intimately involved in the assemblyof MHC class I molecules and in the loading of MHC class Imolecules with optimal peptides for presentation to CD8+

T cells. Their exact molecular roles are, however, unknown. Thestructure of calnexin is the first of several cofactors involved inthe assembly of MHC class I molecules (which also includeTAP, tapasin, ErP57 and calreticulin) to be solved, and providesa structural framework in which to formulate models of calnexinand calreticulin function in class I assembly.Findings: The structure of the proteinase-K-resistant core ofcalnexin (comprising residues 1−482 and lacking residues483−593 which spans the transmembrane and cytoplasmicdomains) was solved to 2.9 Å. The structure was generated forresidues 61−458 only. The molecule appeared fairly flexible as evidenced by high R and B factors, difficulty in assigning certain regions (especially in the region 92−101 and 262−270)and the observation that 15% of the side-chains were disor-dered. The fragment adopts a swan-neck gourd-like structurewith a globular domain comprising amino- and carboxy-terminalregions and a hairpin protrusion comprising the proline-richdomain extending 140 Å away from this globular body. The latteris likely to be flexible, and it is involved in all the major crystalcontacts. A carbohydrate-binding site was mapped (with D-glu-cose) to the globular domain. A putative calcium-binding site

ImmunologyPaper alert

Contents (chosen by)

1 Antigen processing and recognition (Elliott)2 Innate immunity (Bonneville)2 Lymphocyte development (Kruisbeek)3 Tumour immunology (Walker)4 Lymphocyte activation and effector functions (Essayan)5 Immunity to infection (Glaichenhaus and Vyakarnam)7 Immunogenetics (Casanova)7 Immunotherapy (Liu)7 Transplantation (Auchincloss, Waneck and LeGuern)9 Allergy and hypersensitivity (Akdis)9 Autoimmunity (Green)

Antigen processing and recognition

was also mapped to this domain (involving aspartate residuesin both the amino- and carboxy-terminal regions of the mole-cule). Interestingly, no calcium-binding site was found in theP domain as has been previously suggested from in vitro data.

Selected by Marc BonnevilleInstitut de Biologie, Nantes, France


• Recognition of double-stranded RNA and activation ofNF-κκB by Toll-like receptor 3. Alexopoulou L, Holt AC,Medzhitov R, Flavell RA: Nature 2001, 413:732-738.Significance: Double-stranded RNA (dsRNA) is a viral molecular pattern that triggers several innate responses throughactivation of intracellular targets, such as dsRNA-dependentprotein kinase (PKR). The existence of additional dsRNA-induced activation pathways is suggested by the persistence ofinnate responses against dsRNA and viruses in PKR-deficientmice. This study identifies for the first time an extracellularreceptor for dsRNA-recognition, which plays an important rolein the induction of type I interferons and inflammatory cytokinesby innate cells. It also extends the universe of microbial patternsrecognized by Toll-like receptors (TLRs), a family of highly conserved innate receptors shared by insects and mammals.Findings: TLR3 transfectants, unlike untransfected cells orcells transfected with other human TLRs, specifically respondto poly(I:C), a synthetic dsRNA analogue. Compared with wild-type (WT) cells, macrophages from TLR3-deficient mice showstrongly reduced production of type I interferons and inflamma-tory cytokines in response to poly(I:C). Moreover, unlike theirWT counterparts, B cells from TLR3-deficient mice show noresponse to poly(I:C) or viral dsRNA. Poly(I:C)-inducedcytokine production is dependent on MyD88, an adaptor pro-tein common to all TLRs. However, dsRNA-induced maturationof dendritic cells, and activation of nuclear factor (NF)-κB andmitogen-activated protein (MAP)-kinases are induced via aTLR3-dependent but a MyD88-independent pathway.

•• Rae1 and H60 ligands of the NKG2D receptor stimulatetumour immunity. Diefenbach A, Jensen ER, Jamieson AM,Raulet DH: Nature 2001, 413:165-171.Significance: This study, which could have important implications in the design of tumour vaccines, describes a novelmechanism of tumor immunity mediated by NK cells and T cells.Findings: NKG2D is a lectin-like costimulatory receptorexpressed by NK cells, γδ T cells, CD8+ αβ T cells and activatedmacrophages. Several NKG2D ligands related to class I MHCmolecules have been identified, including the H60 minor histo-compatibility gene product and members of the retinoic acidearly-inducible gene (Rae)-1 family. It is shown here that ectopicexpression of H60 or Rae-1β molecules in several syngeneictumor cells (the EL4 and RMA T-cell tumors and the B16-BL6melanoma) leads to rapid tumor rejection, which is mediated byNK and/or CD8+ T cells. Moreover H60- or Rae-1β-expressingtumors induce a specific CD8+ T cell mediated memoryresponse that protects mice from subsequent challenges withtumors of the same type but lacking NKG2D ligands.

• Final steps of natural killer cell maturation: a model of type1-type 2 differentiation? Loza MJ, Perussia B:Nat Immunol 2001, 2:917-924.

Significance: T cells and NK cells can be split into subsetswith distinct functions and cytokine profiles: type 1 cells, whichproduce IFN-γ, take part in immunity against intracellularpathogens whereas type 2 cells, which produce IL-4, -5 and-13, participate in responses against parasites and allergens.Our current view is that these subsets are generated along distinct pathways. This paradigm is challenged by the presentstudy, which demonstrates a direct precursor-to-product relationship between type 2 and type 1 NK cells.Findings: IL-4 promotes the proliferation of human NK cellsand T cells that produce IL-13, whereas IL-12 allows the accumulation of IFN-γ-producing cells that does not depend oncell proliferation. Moreover, whereas type 2 (IL-13-producing)NK-cell clones can differentiate into type 1 (IFN-γ-producing)cells when cultured in IL-12, type 1 NK cells cannot revert totype 2 NK cells, even in the presence of IL-4. Together theseresults indicate that type 2 and type 1 NK cells represent twosteps of a linear differentiation pathway.

Selected by Ada KruisbeekThe Netherlands Cancer Institute, Amsterdam, The Netherlands


• BAFF-R, a newly identified TNF receptor that specificallyinteracts with BAFF. Thompson JS, Bixler SA, Qian F, Vora K,Scott ML, Cachero TG, Hession C, Schneider P, Sizing ID,Mullen C et al.: Science 2001, 293:2108-2111.• An essential role for BAFF in the normal development of Bcells through a BCMA-independent pathway. Schiemann B,Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S,Dobles M, Frew E, Scott ML: Science 2001, 293:2111-2121.Significance: After differentiation and selection in the bonemarrow, newly formed B cells migrate to the peripheral lymphoid organs. How the subsequent fate of peripheral B-cellfate is regulated has been the topic of many studies. Among thenumerous signals crucial for survival of mature B cells are thoseresulting from surface expression of the B-cell antigen receptor(BCR), and these two papers in Science now identify the novelTNF-like ligand BAFF (B-cell activating factor) and its receptor,BAFF-R, as principal regulators of B-cell fate.Findings: In the study by Thompson et al., a novel receptor forBAFF is identified, termed BAFF-R. Two TNF-R-family members(BCRA and TACI) had earlier been shown to bind BAFF, butthese are not specific for BAFF, unlike BAFF-R. An experimentof nature then helped in nailing down the functional importanceof BAFF-R: the murine BAFF-R gene was localized to the siteof the genomic defect of A/WSnJ mice, which have a severeperipheral-B-cell defect. Indeed, the BAFF-R locus is disruptedin A/WSnJ mice. Although the full characterization of theA/WySnJ mutation in the BAFF-R gene remains to be performed, the B-cell phenotype of A/WySnJ mice is qualitativelysimilar to that of BAFF-deficient mice, which is described in thepaper by Schiemann et al.: these mice exhibit normal B-celldevelopment in the bone marrow, but severe reduction of allperipheral B-cell subsets (with the exception of B1 cells). Inaddition, BAFF-deficient mice have only negligible IgMresponses after challenge with T-cell-dependent and T-cell-independent antigens. Together, these studies establish theimportance of BAFF and BAFF-R in the survival and maturationof B cells that have just emerged from the bone marrow.

2 Paper alert

Innate immunity

Lymphocyte development

• Promiscuous gene expression in medullary thymicepithelia cells mirrors the peripheral self. Derbinski J,Schulte A, Kyewski B, Klein L: Nat Immunol 2001,2:1032-1039.Significance: T-cell tolerance to self-antigens is often thoughtto be accomplished during either of two stages of develop-ment: in the thymus (through exposure to those self-antigenspresented by thymic antigen-presenting cells) or in the periphery (through exposure to antigens whose expression isconfined to specific tissues). The problem with this view is thatit disregards the increasing evidence for ‘promiscuous geneexpression’ specifically in the thymus, and for a functional rolefor promiscuous gene expression in the induction of T-cell tolerance: allelic or strain-specific variations in intrathymicexpression of a number of ‘tissue-specific’ antigens have beencorrelated with susceptibility to organ-specific autoimmunity,and intrathymic expression of autoantigens correlates withresistance to autoimmune disease. The present study identifiesmedullary thymic epithelial cells (mTECs) as a specialized celltype that expresses a broad range of tissue-specific antigens.Findings: Four distinct subsets of thymic stromal cells wereenriched to high purity: mTECs, cortical TECs, dendritic cellsand macrophages. Transcription of some 20 tissue-specific anti-gens was detectable in mTECs; some antigens were alsodetectable in some of the other thymic stromal subsets, but theirexpression pattern did not correlate with structural or functionalcommonalties or with the derivation of the respective peripheraltissue. Other epithelial cell types did not express such a broadrange of tissue-antigen expression, which thus appears to be adistinctive characteristic of mTECs. These studies were per-formed in strains including C57BL/6, NOD, and RAG2−/− mice.Although no evidence was found that intrathymic expression of particular genes evolved from the necessity to maintain tolerance to their gene products, the potential immunologicalimplications of these findings are enormous. Tumor antigens thatwere previously thought of as attractive targets for T-cell-basedanti-tumor therapy because of their tissue-specific expressionmay have induced some tolerance through thymic expression.Also, antigens in mTECs may affect the generation of regulatoryT cells. Overall, these findings show that many self-antigens arenot as spatially or temporally separated from the immune systemas is often thought.

• Pre-B cell receptor signaling mediates selective responseto IL-7 at the pro-B to pre-B cell transition via an ERK/MAPkinase-dependent pathway. Fleming HE, Paige CJ: Immunity2001, 15:521-531.Significance: This study examines the interplay between theIL-7 receptor (IL-7R) and the pre-BCR (pBCR) signaling pathways in early B-cell development. Both receptors havebeen implicated in survival, proliferation and differentiation ofB-lineage cells, but specific mechanisms describing their roleshave yet to be defined. Earlier experiments suggested thatresponsiveness of pre-B cells to IL-7 requires a functionalpBCR, and the present study defines how both these pathwaysregulate the pro-B→pre-B-cell transition checkpoint.Findings: First, it is shown that the ability of pre-B cells to proliferate in response to IL-7 is correlated with the presence ofand signaling through the pBCR. This results in specific activation of the ERK pathway and not of other MAPK pathways.Moreover, ERK activation is required for the IL-7-driven proliferation of pre-B cells, as shown in experiments with pharmacological inhibitors of the ERK pathway. Differentiation,

on the other hand, proceeds undisturbed. Finally, constitutiveERK phosphorylation correlates with pBCR expression andresponsiveness to IL-7 in a panel of cell lines. Together, theresults suggest a model by which enhanced responsiveness toIL-7 ensures that only pBCR-expressing B-cell precursors cancontinue to develop past the pro-B→pre-B checkpoint.

• A defect in central tolerance in NOD mice. Kishimoto H,Sprent J: Nat Immunol 2001, 2:1025-1031.Significance: One of the central questions in T-cell tolerance toself-antigens concerns the extent to which central (i.e.intrathymic) and peripheral mechanisms contribute to the tolerant state (see also Derbinski et al., above). This is particu-larly relevant in the NOD strain of mice, whose predispositionto type 1 diabetes is thought to reflect defects in peripheral tolerance mechanisms. The problem with this hypothesis is thatNOD mice not only exhibit T-cell-mediated destruction of pancreatic β cells, but also lack self-tolerance to a spectrum ofother self-antigens, including myoglobin and ribosomal proteins. Indeed, NOD mice develop generalized autoimmunedisease, affecting multiple organs. This study therefore examines the efficacy of central tolerance in NOD mice.Findings: Negative selection of semi-mature thymocytes(HSAhiCD4+CD8−) from NOD mice was severely impairedin vitro and in vivo. For instance, crosslinking NOD mouse thymocyte subsets using anti-TCR and anti-CD28 reveals aselective defect in the HSAhiCD4+CD8− subset, but not in aless-mature thymocyte subset. This distinguishes NOD thymo-cytes from those of several normal and autoimmune strains, andapplied to Fas-independent and Fas-dependent apoptosis.Importantly, the defect was independent of IAβg7, the uniqueMHC class II allele expressed in NOD mice. In vivo negativeselection following injection of SEB is severely impaired inHSAhiCD4+CD8− NOD thymocytes. This is not a consequenceof TCR hyporesponsiveness but there is an interesting correla-tion between resistance to Fas-dependent apoptosis afterTCR/CD28 ligation and increased cFLIP expression inHSAhiCD4+CD8− NOD thymocytes. This cannot be the wholeexplanation for the observed defect but, together, the data provide direct evidence that NOD mice have a defect in centraltolerance. This is the most important conclusion of the studyand it indicates a need for reinterpretation of the existing dataon peripheral-tolerance dysregulation in NOD mice.

Selected by Paul R WalkerUniversity Hospital Geneva, Geneva, Switzerland


•• Ectopic expression of retinoic acid early inducible-1gene (RAE-1) permits natural killer cell-mediated rejectionof a MHC class I-bearing tumor in vivo. Cerwenka A,Baron JL, Lanier LL: Proc Natl Acad Sci USA 2001,98:11521-11526.•• Rae1 and H60 ligands of the NKG2D receptor stimulatetumour immunity. Diefenbach A, Jensen ER, Jamieson AM,Raulet DH: Nature 2001, 413:165-171.•• Regulation of cutaneous malignancy by γγδδ T cells.Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E,Filler R, Hobby P, Sutton B, Tigelaar RE, Hayday AC: Science2001, 294:605-609.

Paper alert 3

Tumour immunology

Significance: NK cell and cytotoxic T lymphocyte (CTL) activity is proposed to be augmented by interaction of theNKG2D receptor with its ligands (including MICA/B and ULBPin humans; RAE-1 and H60 in mice), which are overexpressedby certain tumour cells. However, this proposal has, to date,been based on in vitro data. In these new publications, RAE-1and H60 are shown for the first time to influence the antitumourimmune response in vivo, demonstrating the importance ofNKG2D ligation for innate and adaptive immune effectors (NKcells, and γδ and αβ T cells).Findings: In the papers by Cerwenka et al. and Diefenbachet al., function of NKG2D ligands is assessed by ectopicexpression of high levels of RAE-1 or H60 in tumour cells thatare then implanted in vivo. Cerwenka et al. found that RAE-1expression sensitised RMA (H-2b+) or RMA-S (H-2b−) tumourcells to NK cell mediated rejection, without any generation of tumour-specific memory. These results are similar to those ofDiefenbach et al., who observed NK cell mediated rejection ofRAE-1- or H60-transduced RMA, RMA-S, EL4 or B16 tumourcells. However, in this study, even when rejection of the primaryRAE-1+ or H60+ tumour was NK cell mediated, CD8+ T cellswere also stimulated and were able to specifically protect mice from secondary challenge with wild-type tumours. In the experiments of Girardi et al., a different approach was adopted.Expression of RAE-1 and H60 was detected in vivo in papillo-mas and carcinomas induced by chemical carcinogens. Tumourformation was enhanced in mice deficient in either αβ or γδT cells, but the importance of each population depended uponthe particular chemical carcinogens used. In vitro, γδ T cellmediated killing of RAE-1+ tumour cells was inhibited by antibodies to γδ TCR or NKG2D, and by soluble RAE-1.

• Tumor-specific immunity and antiangiogenesis generatedby a DNA vaccine encoding calreticulin linked to a tumorantigen. Cheng WF, Hung CF, Chai CY, Hsu KF, He L, Ling M,Wu TC: J Clin Invest 2001,108:669-678.Significance: Multimodality rather than single modality therapiesfor cancer are the most likely to have a significant clinical impact.The challenge is to combine mutually compatible therapies andto devise appropriate readouts to aid their optimisation. Thisstudy makes strides in achieving this in a mouse model employ-ing antiangiogenesis and antigen-specific immunotherapy.Findings: Cheng et al. investigated a tumour vaccine based onDNA encoding calreticulin (CRT) linked to a model tumour antigen (from human papilloma virus type16) that generatedimpressive antitumour immunity (both prophylactic and thera-peutic). The CRT component of the vaccine not only enhancedspecific CD8+ T cell mediated antitumour immunity in immuno-competent mice, but also reduced the number of tumournodules and tumour microvessel density in nude mice.

• Immunotherapy through TCR gene transfer. Kessels HW,Wolkers MC, van den Boom MD, van der Valk MA,Schumacher TN: Nat Immunol 2001, 2:957-961.• Circumventing tolerance to a human MDM2-derivedtumor antigen by TCR gene transfer. Stanislawski T,Voss RH, Lotz C, Sadovnikova E, Willemsen RA, Kuball J,Ruppert T, Bolhuis RL, Melief CJ, Huber C et al.: Nat Immunol2001, 2:962-970.Significance: Certain tumour-associated antigens in humancancer are promising targets for antitumour T cells, buthigh-avidity T cells may be lacking from the autologous repertoire because of self tolerance. These papers elegantly

demonstrate that transferring genes for the α and β chains ofthe TCR can generate T cells with functional antitumour activityin vitro and in vivo.Findings: In both studies, transfer of TCR genes was achievedby retroviral delivery. Kessels et al. expressed a TCR specific foran influenza epitope restricted by H-2Db. Although only5%–15% of cells expressed the desired TCR after retroviralinfection, these cells underwent antigen-driven expansion afteradoptive transfer in vivo, to yield fully functional T cells capableof mediating antigen-specific tumour rejection. Stanislawskiet al. investigated TCR gene transfer in order to target specificity to a human tumour-associated antigen, MDM2. AnHLA-A2-restricted CTL epitope was identified from MDM2, andshown to be expressed in a wide range of tumours. However,high-avidity CTLs specific for this epitope were not present inthe two HLA-A2+ donors tested, presumably because of lowexpression levels of MDM2 by normal tissues, sufficient toinduce clonal deletion. A CTL clone from an HLA-A2-transgenicmouse was used to provide genes encoding an MDM2-specificTCR, which was partially humanised, then transferred intohuman T cells. After enrichment for MDM2-reactive cells, theseT cells specifically lysed peptide-pulsed targets as well ashuman tumour cell lines constitutively expressing MDM2.

Selected by David EssayanUS Food and Drug Administration, Rockville, MD, USA


• Duration of nuclear NF-κκB action regulated by reversibleacetylation. Chen L-f, Fischle W, Verdin E, Greene WC:Science 2001, 293:1653-1657.Significance: A novel mechanism for active downregulation ofNF-κB signaling.Findings: The RelA subunit of NF-κB is a target for signal-coupled acetylation by p300 and CBP; acetylated RelA bindspoorly to IκBα, effectively prolonging its nuclear residence timeand activity as a transcriptional regulator. RelA is deacetylatedby histone deacetylase 3, making NF-κB available for IκBαbinding, inactivation and shuttling from the nucleus to the cytoplasm.

• Gene microarrays reveal extensive differential geneexpression in both CD4+ and CD8+ type 1 and type 2T cells. Chtanova T, Kemp RA, Sutherland APR, Ronchese F,Mackay CR: J Immunol 2001, 167:3057-3063.Significance: The most comprehensive analysis of differentialgene expression between type 1 and type 2 cells to date.Findings: T cells expressed a high number of genes and ESTsoverall (approximately 11 000), but the vast majority (>90%)were expressed similarly between type 1 and type 2 cells.Although many of the differentially expressed genes conformedto the expected pattern of cytokines, receptors and transcriptionfactors, a surprising number of unexpected or uncharacterizedgenes were also identified. Differential expression patternsbetween Tc and Th subtypes were similar. Expression patternsfor selected genes were confirmed by real-time PCR.

• BAFF-R, a newly identified TNF receptor that specificallyinteracts with BAFF. Thompson JS, Bixler SA, Qian F, Vora K,Scott ML, Cachero TG, Hession C, Schneider P, Sizing ID,Mullen C et al.: Science 2001, 293:2108-2111.

4 Paper alert

Lymphocyte activation and effector functions

• An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway.Schiemann B, Gommerman JL, Vora K, Cachero TG,Shulga-Morskaya S, Dobles M, Frew E, Scott ML: Science2001, 293:2111-2114.Significance: Signaling through BAFF and BAFF-R is criticalfor B-cell development.Findings: BAFF (TALL-1, THANK, BLyS, zTNF4) engagesBCMA and TACI, but its effects on B-cell maturation/survivalcan not be readily ascribed to signaling through these tworeceptors. Thompson et al. identify a third receptor specific forBAFF, called BAFF-R. The A/WySnJ mouse, with a phenotypesimilar to the BAFF-deficient mouse, exhibits a complex mutation in the BAFF-R gene. Schiemann et al. provide a morecomplete description of the BAFF−/− phenotype, whichincludes severe B-cell depletion from all secondary lymphoidcompartments, minimal effect on bone marrow or peritoneal B1cell populations, and a variety of peripheral-B-cell functionaldefects; by contrast, BCMA−/− mice displayed normal-appearing B-cell compartments.

• T cell activation in rheumatoid synovium is B cell dependent. Takemura S, Klimiuk PA, Braun A, Goronzy JJ,Weyand CM: J Immunol 2001, 167:4710-4718.Significance: Specific disease processes may be regulated byrestricted sets of APCs. This manuscript is a compellingdemonstration with potential therapeutic implications.Findings: Microdissected synovial follicular T cells adoptivelytransferred into synovium−SCID-mouse chimeras retainedproinflammatory activity. Synovia lacking resident B cells failedto support proinflammatory activity, despite the presence ofT cells, macrophages and dendritic cells. Active B-cell-specificdepletion of synovia with anti-CD20 was associated with disruption of synovial tertiary lymphoid architecture and inhibition of T-cell proinflammatory activity.

• Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Jutel M,Wantanabe T, Klunker S, Akdis M, Thomet OAR, Malolepszy J,Zak-Nejmark T, Koga R, Kobayashi T, Blaser K, Akdis CA:Nature 2001, 413:420-425.Significance: The first description of an important regulatorypathway for CD4+ T-cell subsets.Findings: H1 receptors were predominantly expressed on Th1cells, whereas H2 receptors were predominantly expressed onTh2 cells. Histamine signaling through H1 receptors in Th1cells resulted in enhanced proliferation, cytokine secretion andB-cell help through a calcium-dependent pathway whereas, inTh2 cells, histamine signaling through H2 receptors resulted ininhibition of proliferation, cytokine secretion and B-cell helpthrough a cAMP-dependent pathway. Studies with receptorknockout mice and selective receptor antagonists corroboratedthese findings.

• Rules of chemokine receptor association with T cell polarization in vivo. Kim CH, Rott L, Kunkel EJ, Genovese MC,Andrew DP, Wu L, Butcher EC: J Clin Invest 2001,108:1331-1339.• Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 byCD4+CD25+ regulatory T cells. Iellem A, Mariani M, Lang R,Recalde H, Panina-Bordignon P, Sinigaglia F, D’Ambrosio D:J Exp Med 2001, 194:847-854.

Significance: The most comprehensive assessment to date ofchemokine receptors as potential markers of CD4 phenotypes.Findings: Kim et al. demonstrated that the expression of eachchemokine receptor on CD4+ T cells defined a characteristicpool of cells and, although no one receptor was specific for agiven phenotype, specific patterns of receptor expression werecharacteristic of enriched populations of a given phenotype.Specifically, CXCR3+CCR4− cells were predominantly Th1whereas CXCR3–CCR4+ cells were predominantly Th2.CCR7 showed little selectivity and other ‘Th1’ chemokinereceptors showed little or no selectivity unless associated withCXCR3 expression. Iellem et al. demonstrated that regulatoryT cells selectively expressed CCR4 and CCR8 and that thiscellular phenotype responds to ligands of these receptors,including CCL1 and CCL22.

Selected by Nicolas GlaichenhausInstitut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France


•• Priming of memory but not effector CD8 T cells by akilled bacterial vaccine. Lauvau G, Vijh S, Kong P, Horng T,Kerksiek K, Serbina S, Tuma RA, Pamer EG: Science 2001,294:1735-1739.Significance: In the case of many intracellular pathogens,immunization with killed or inactivated organisms fails to inducea protective immune response. In this paper, Lauvau et al.provide an interesting explanation for this phenomenon.Findings: In contrast to mice immunized with heat-killedListeria monocytogenes (HKLM), mice infected with live bacteria developed a protective, long-lived CD8+-T-cellresponse. Despite this result, HKLM-immunized mice mounteda memory CD8+-T-cell response that was indistinguishable insize from the one detected in mice immunized with live bacteria.Further experiments showed that the lack of protective immunity in HKLM-immunized mice was not the result of animpaired CD4+-T-cell response. Furthermore, whereas CD8+

T cells from live-bacteria-immunized mice expressed cytolyticactivity and secreted IFN-γ, those from HKLM-immunized mice exhibited a failure to do so, further suggesting that they had notacquired effector functions.

•• The plasticity of dendritic cell responses to pathogensand their components. Huang Q, Liu N, Majewski P,Schulte AC, Korn JM, Young RA, Lander ES, Hacohen N:Science 2001, 294:870-875.Significance: Dendritic cells (DCs) play a key role in the development of immune responses against pathogens such asbacteria, viruses and fungi. To discriminate between thesepathogens, DCs express different pattern-recognition of receptors (PRRs), which are specific for molecular determinantsexpressed by a defined class of pathogens. By searching for cellular genes whose level of expression is modified upon infectionof DCs with influenza virus, Escherichia coli or Candida albicans,Huang et al. provide new insights into the mechanisms by whichDCs induce tailored pathogen-specific immune responses.Findings: Using oligonucleotide microarrays, the authors havefound that 1330 genes out of 6800 were upregulated uponinfection of human monocyte-derived DCs with at least one ofthe tested pathogens. Whereas some genes were regulated by

Paper alert 5

Immunity to infection

all pathogens, others were regulated by a unique pathogen.Thus, DCs not only are capable of generating a core responseto any pathogen, but also exhibit stimulus-specific maturationand activation.

• Infection of dendritic cells by murine cytomegalovirusinduces functional paralysis. Andrews DM, Andoniou CE,Granucci F, Ricciardi-Castagnoli P, Degli-Esposti MA:Nat Immunol 2001, 2:1077-1084.Significance: DCs play a key role in the development of immuneresponses against pathogens. To evade the immune system, somepathogens have evolved to interfere with DC function, a phenom-enon resulting in immunosuppression. In this paper, Andrews et al.show that interference with DCs is one of the tricks used by themurine cytomegalovirus (MCMV) to prevent the development of aprotective response and to establish persistent infection.Findings: In this study, the authors have shown that MCMV caninfect DCs in vitro and in vivo, and productively replicates inDCs at least in vitro. MCMV was also demonstrated to reducethe endocytic capacity of DCs, to induce the downregulation ofadhesion, homing, MHC and costimulatory molecules, and toreduce the ability of DCs to respond to maturation stimuli andto simulate the proliferation of naive T cells in vitro.

•• Specific and nonspecific NK cell activation during virusinfection. Dokun AO, Kim S, Smith HR, Kang HS, Chu DT,Yokoyama WM: Nat Immunol 2001, 2:951-956.•• Analysis of in situ NK cell responses during viral infection. Dokun AO, Chu DT, Yang L, Bendelac AS, Yokoyama WM:J Immunol 2001, 167:5286-5293.Significance: Although NK cells have been shown to play a critical role in the control of MCMV infection, it was not clear howthe different subsets of NK cells could participate in the clearanceof the virus. Likewise, it remained to be established whetherMCMV infection induced NK cells to accumulate in lymphoid tis-sues and/or at the sites of viral replication. In these two papers,Yokoyama and his colleagues provide answers to these questions.Findings: Several inhibitor and activator receptors have beendescribed at the surface of NK cells. Using a combination ofgenetic and immunologic approaches, Yokayama and his col-leagues have recently shown that clearance of MCMV in micewas dependent on a subset of NK cells that expressed the acti-vation receptor Ly49H. The authors now report that MCMV, butnot vaccinia virus, induces the selective proliferation of Ly49H+

NK cells, resulting in their accumulation in the spleen and theliver. This phenomenon was observed on day 6 after infectionbut was preceded by a nonspecific phase of activation in whichseveral NK-cell subsets proliferated and secreted IFN-γ. Inagreement with this latter finding, the authors found that NKcells that were recognized by the 4D11 monoclonal antibody(anti-Ly49G2) were associated with MCMV-infected cells inthe spleen and the liver on day 3 after infection.

• Immunopathology in RSV infection is mediated by a discrete oligoclonal subset of antigen-specific CD4+ T cells.Varga SM, Wang X, Welsh RM, Braciale T: Immunity 2001,15:637-646.Significance: Respiratory syncytial virus (RSV) infection is theleading cause of bronchiolitis and viral pneumonia in infants andyoung children. There is currently no safe and effective RSV vaccine. In the first vaccine trials using formalin-inactivated RSV,some children died and these children were found to have devel-oped pulmonary eosinophilia and peribronchiolar infiltration. A

similar lung pathology was observed in mice which had beenimmunized with a recombinant vaccinia virus expressing theRSV G glycoprotein and challenged by intranasal infection withRSV. In this paper, the authors provide an interesting explanationfor this phenomenon.Findings: In mice immunized with the RSV G protein and challenged with RSV, 30% of the G-specific CD4+ T cells in thelungs expressed Vβ14 and exhibited similar CDR3β regions.T cells from immunized mice secreted Th2 cytokines upon in vitrostimulation with anti-Vβ14 monoclonal antibody. Furthermore,depletion of Vβ14+ T cells after vaccination prevented the pulmonary eosinophilia induced by RSV. The authors concludedthat Vβ14+ T cells represent the predominant population of effectorT cells that accumulate at the site of infection in RSV-infectedmice. In mice that had been immunized with the RSV G proteinprior to challenge with the virus, this oligoclonal population ofT cells is responsible for the Th2-driven immunopathology.

• Sandfly maxadilan exacerbates infection withLeishmania major and vaccinating against it protects againstL. major infection. Morris RB, Shoemaker CB, David JR,Lanzaro GC, Titus RG: J Immunol 2001, 167:5226-5230.Significance: Bloodfeeding arthropods transmit many of theworld’s most serious infectious diseases. In several cases,arthropod saliva has been shown to enhance the infectivity ofpathogens that the arthropod transmits because it containsmolecules that affect blood flow and modulate the immuneresponse of the host. Despite these data, the saliva moleculesthat are responsible for this phenomenon have been poorlycharacterized. This study is the first to report the identificationof such a molecule.Findings: The authors have shown that a neuropeptide namedmaxadilan, which is present in the saliva of the arthropod vector, exacerbates infection with L. major to the same degreeas whole saliva. Moreover, vaccination with maxadilan protectsmice against a subsequent infection with L. major.

Selected by Anna VyakarnamKing’s College London, London, UK


• Differential regulation of antiviral T cell immunity results instable CD8+ but declining CD4+ T-cell memory. Homann D,Teyton L, Oldstone MBA: Nat Med 2001, 7:913-919.Significance: This paper provides important insights to themechanisms that regulate CD4+ and CD8+ T cell immunity.Antigen (LCMV)-specific CD8+ and CD4+ responses are shownto be highly co-ordinated. However, CD4+ T cell responses weresmaller and decayed progressively despite intact immunity. Thissuggests that CD4+ T cell dependent immunity relies on relativelysmall numbers of memory CD4+ T cells, but their loss in diseaseslike HIV or cancer, or in old age can lead to potential impairmentof the protective immune response.Findings: Three well-recognised phases of T cell responseswere measured: expansion or activation, contraction/death andmaintenance or memory. LCMV-specific MHC class I and IIrestricted responses in C57BL/6 mice were monitored over a2.5-year period using tetramers (Tet) of peptide with MHC classI and II, respectively. CD8+ Tet-specific IFNγ+ or TNFα+

responses remained constant through the three phases. In contrast, the CD4+ T cell response was 20-fold lower than theequivalent CD8+ T cell response, peaked at 10 days and neverstabilised. Measurement of proliferation and size of the responseshowed that 75% of CD8+ T cells and 20% of total CD4+

6 Paper alert

T cells were specific. There was a gradual shift from predominantIFNγ production to IFNγ and TNFα production in memory CD4+

and CD8+ T cells; this was maintained indefinitely. Aged memory CD4+ T cells did not differ from early effector popula-tions in terms of response kinetics or avidity. Antigen-specificCD4+ and CD8+ T cells had lower survival capacity than naïvecounterparts of undefined specificity and specific CD4+ T cellssurvived less well than CD8+ T cells. Both subsets showed similar doubling times in vivo after primary challenge and recallresponses were almost identical to the primary challenge.

• Naïve CD4 T cells inhibit CD28-costimulated R5 HIV replication in memory CD4 T cells. Mengozzi M,Malipatolla M, De Rosa SC, Herzenberg LA, Roederer M:Proc Natl Acad Sci USA 2001, 98:11644-11649.Significance: Stimulation of CD4+ T cells with anti-CD3 and-CD28 has been shown to induce β chemokine mediateddownregulation of the HIV coreceptor CCR5 and thus confersresistance to infection by R5 HIV strains. This paper shows thatnaïve CD4+ T cells can suppress R5 HIV-1 replication in memory CD4+ T cells in a β-chemokine-independent manner,with therapeutic implications. The observations extend otherwork in the literature showing multiple mechanisms of HIVresistance in CD4+ T cells.Findings: CD4+ T cells from the blood of HIV-naïve individualswere separated into naïve cells (CD45RA+CD62L+) and twodistinct populations of memory cells: M1 (CD45RA−CD62L−)and M2 (CD45RA−CD62L+). Memory cells are known to bemore efficiently infected than naïve cells by an X4 HIV-1 strain.CCR5 was expressed preferentially on M1 cells than M2 cellsand infection by R5 HIV-1 of M1 cells was greater. Viral inhibi-tion was influenced by cell type and to a lesser extent by thestrength of the stimulatory signal. The high level of replication inM1 cells occurred despite β-chemokine production and down-regulation of CCR5. Whereas purified M1 cells supported R5replication, mixing experiments of naïve and memory cellsshowed that M2 cells inhibited virus partially in M1 cells, butnaïve cells completely inhibited virus replication in M1 cells.This capacity was specific for R5 but not X4 HIV, was notaffected by previous exposure to virus and was β-chemokine-independent. Therefore both chemokine-dependent and-independent mechanisms can inhibit R5 HIV-1 in blood-derived CD4+ T cells.

Selected by Jean-Laurent CasanovaLaboratory of Human Genetics of Infectious Disease, Necker-Enfants

Malades Medical School, Paris, Francee-mail: [email protected]

• Mutations of CD40 gene cause an autosomal recessiveform of immunodeficiency with hyper IgM. Ferrari S,Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M,Avanzini MA, Marconi M, Badolato R, Ugazio AG et al.:Proc Natl Acad Sci USA 2001, 98:12614-12619.Significance: This is the first identification of human inheritedCD40 deficiency, providing a third molecular etiology for the hyper-IgM syndrome; it is thus designated as hyper-IgM type 3 (HIGM3).Findings: Three children with the hyper-IgM syndrome and alack of mutation in CD154/CD40-ligand (which is defective inHIGM1) or activation-induced cytidine deaminase (which is

defective in HIGM2) were investigated. The clinical phenotyperesembled that of HIGM1 patients owing to the occurrence ofopportunistic infections. CD40 molecules were not detectableon the surface of the patients’ peripheral blood B cells andmonocytes. There was a lack of CD40-mediated proliferationand immunoglobulin class-switch of B cells. Two relatedpatients had a CD40 Cys→Arg homozygous substitution in theextracellular cysteine-rich domain of CD40, and the thirdpatient had a homozygous intron splice mutation, as validatedin vitro by exon trapping. This report provides the third geneticetiology for the hyper-IgM syndrome. Like HIGM2, HIGM3 follows an autosomal recessive mode of inheritance. Clinicallyand immunologically, however, the patients are undistinguish-able from patients with X-linked HIGM1.

Selected by Yang LiuOhio State University, Columbus, OH, USA


•• Impaired recruitment of bone-marrow-derived endothelialand hematopoietic precursor cells blocks tumor angio-genesis and growth. Lyden D, Hattori K, Dias S, Costa C,Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte Let al.: Nat Med 2001, 7:1194-1201.Significance This study is the first demonstration that recruitmentof vascular-endothelial-cell growth factor (VEGF)-responsive bonemarrow (BM)-derived precursors is necessary and sufficient fortumor angiogenesis and suggests new clinical strategies to blocktumor growth.Findings: The previously reported defects in tumor angiogenesis and growth in the Id mutant mice are due to impairedVEGF-driven mobilization of VEGFR2+ circulating endothelialprecursors (CEPs) and impaired proliferation and incorporationof VEGFR1+ cells. Tumor angiogenesis and growth in the Id-mutant mice can be restored by transplantation with eitherBM or VEGF-mobilized wild-type stem cells.

• Identification of the CD4+ T cell as a major pathogenicfactor in ischemic acute renal failure. Burne MJ, Daniels F,El Ghandour A, Mauiyyedi S, Colvin RB, O’Donnell MP,Rabb H: J Clin Invest 2001, 108:1283-1290.Significance: This clear-cut demonstration of critical involvementof T cells in the pathogenesis of ischemic acute renal failure(ARF) makes ARF a disease to be tackled by immunotherapy.Findings: ARF in mice is prevented by a deficiency in T cells.The adoptive transfer of CD4+, but not of CD8+, T cells reconstitutes ARF in nude mice. Moreover, the development ofARF depends on both IFN-γ and CD28.

Selected by Hugh Auchincloss Jr*, Gerry Waneck and Christian LeGuernMassachusetts General Hospital, Boston, MA, USA

*e-mail: [email protected]

• An antagonist IL-15/Fc protein prevents costimulationblockade-resistant rejection. Ferrari-Lacraz S, Zheng XX,Kim YS, Li Y, Maslinski W, Li XC, Strom TB: J Immunol 2001,167:3478-3485.

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Immunogenetics

Immunotherapy

Transplantation

Significance: This study provides an important new reagent forthe induction of tolerance and highlights the importance ofIL-15 in T-cell activation, especially of CD8+ T cells.Findings: The investigators developed an IL-15-mutant fusionprotein that has both cytotoxic and antagonist properties forcells expressing the IL-15 receptor. When used in conjunctionwith CTLA4−Ig, the two fusion proteins together producedindefinite survival in a stringent model of allogeneic transplan-tation in mice.

• Characterization of virus-mediated inhibition of mixedchimerism and allospecific tolerance. Williams MA, Tan JT,Adams AB, Durham MM, Shirasugi N, Whitmire JK,Harrington LE, Ahmed R, Pearson TC, Larsen CP: J Immunol2001, 167:4987-4995.Significance: This study adds a new component to the elements that must be considered when attempting to inducetolerance. Dendritic-cell activation by nonspecific viral infectionmay alter the outcome of some tolerance-induction strategies.Findings: The investigators studied the effect of acute viralinfection on the induction of tolerance in mice. LCMV infectionat the time of induction abrogated the tolerogenic effect ofcombined costimulatory blockade. Infection late, after theinduction of tolerance, did not reverse the condition. The investigators’ studies led them to conclude that viral infectionactivated dendritic cells, providing activation of alternative costimulatory pathways.

• Beneficial effects of targeting CCR5 in allograft recipients.Gao W, Faia KL, Csizmadia V, Smiley ST, Soler D, King JA,Danoff TM, Hancock WW: Transplantation 2001,72:1199-1205.Significance: This study adds another molecule to the list ofchemokines and chemokine receptors that have been shown toplay important roles in allograft rejection.Findings: Prolonged, but not indefinite, cardiac allograft survival was found in mice by using CCR5 knockout recipientsor by blocking CCR5 using antibody treatment. There was noprolongation of survival when knockout mice for MIP-1α orRANTES, two of the high-affinity ligands for CCR5, were used.

• Type 2 dendritic cells (DC2) in peripheral T cell tolerance.Kuwana M, Kaburaki J, Wright TM, Kawakami Y, Ikeda Y:Eur J Immunol 2001, 31:2547-2557.Significance: An important contribution supporting the viewthat the Th2-skewing myeloid dendritic cell type 2 (DC2) cellsmay also have a role in ‘silencing’ antigen-specific peripheralCD4+ T cells.Findings: Tetanus-toxoid-specific CD4+ Th1 cell lines incubatedwith DC2 cells that were pulsed with the cognate antigen failedto proliferate and did not produce IL-2, but secreted IFN-γ andIL-10. As anticipated, this anergic state was reversible by highdoses of IL-2. Similar DC2-cell-dependent anergy was observedin autoreactive CD4+ clones specific for topoisomerase I in scleroderma, suggesting that peripheral DC2 cells are involvedin maintenance of peripheral tolerance to self-antigens.

• Infectious tolerance proceeds through regulatory T cells.Zhai Y, Shen XD, Lehmann M, Busuttil R, Volk HD,Kupiec-Weglinski JW: J Immunol 2001, 167:4814-4820.Significance: These studies demonstrate that anti-CD4-induced tolerance to heart grafts in rats, classicallytermed ‘infectious tolerance’ since it can be transmitted to

naive hosts via T-cell transfer, is mediated by CD4+CD45RC+

regulatory T cells (T-reg).Findings: The authors analyzed in vitro the immune status ofanti-CD4-treated recipients tolerant to allogeneic heart grafts.The persistence of proliferative T cells to donor antigens inthese animals suggested active regulatory mechanisms, whichwere attributed to CD4+CD45RC+ T-reg by surface typing andsuppression assays. Interestingly, T-reg resided in the spleenbut not in lymph nodes, suggesting a compartmentalization ofregulatory and effector T cells.

• Predominance of NK1.1+TCRααββ+ or DX5+TCRααββ+ T cellsin mice conditioned with fractionated lymphoid irradiationprotects against graft-versus-host disease: ‘natural suppressor’ cells. Lan F, Zeng D, Higuchi M, Huie P,Higgins JP, Strober S: J Immunol 2001, 167:2087-2096.Significance: This study shows that CD4+ NKT cells becomethe predominant T-cell subset in mice receiving a nonmyeloab-lative conditioning regimen to establish mixed allogeneicchimerism. These ‘natural suppressor’ cells secrete high levelsof IL-4 and protect hosts against acute lethal GVHD.Findings: After C57BL/6 and BALB/c hosts received fraction-ated irradiation of lymphoid tissues — with marrow shielding incombination with anti-mouse thymocyte serum — CD4+TCRαβ+

cells expressing NK markers increased without expansion from~2% to >90% of all splenic TCRαβ+ cells due to a profounddepletion of NK1.1− and DX5− T cells. Conditioned mice developed stable mixed chimerism and survived long-term afterinfusion with allogeneic bone marrow and peripheral bloodmononuclear cells. Protection against GVHD was achievedwhen wild-type hosts were given IL-4−/− donor marrow,whereas survival was significantly reduced when IL-4−/− hostswere used.

• Dissociation of hemopoietic chimerism and allograft tolerance after allogeneic bone marrow transplantation.Umemura A, Morita H, Li XC, Tahan S, Monaco AP, Maki T:J Immunol 2001, 167:3043-3048.Significance: This study shows that donor-T-cell engraftment isrequired for induction of allograft tolerance, but not for creationof continuous hemopoietic chimerism after allogeneic bone marrow transplantation (BMT), and that a high degree of chimerismis not necessarily associated with specific allograft tolerance.Findings: Allogeneic BMT with bone marrow cells (BMCs) prepared from either knockout mice deficient in both CD4+ andCD8+ T cells or CD3E-transgenic mice lacking both T cells andNK cells maintained a high degree of chimerism, but failed toinduce tolerance to donor-specific wild-type skin grafts.Lymphocytes from mice reconstituted with T cell deficientBMCs proliferated when they were injected into irradiateddonor-strain mice, whereas lymphocytes from mice reconstituted with wild-type BMCs were unresponsive to donoralloantigens. Donor-specific allograft tolerance was restoredwhen donor-type T cells were adoptively transferred to recipient mice given T cell deficient BMCs.

• Membrane lymphotoxin regulates CD8+ T cell-mediatedintestinal allograft rejection. Guo Z, Wang J, Meng L, Wu Q,Kim O, Hart J, He G, Zhou P, Thistlethwaite JR Jr, Alegre MLet al.: J Immunol 2001, 167:4796-4800.Significance: Blocking the CD28/B7 and/or CD154/CD40costimulatory pathways promotes long-term allograft survival inmany transplant models where CD4+ T cells are necessary for

8 Paper alert

rejection. When CD8+ T cells are sufficient to mediate rejection, these approaches fail. This study shows that disruption of membrane lymphotoxin interactions can inhibitcostimulation-blockade-resistant rejection by CD8+ T cells.Findings: Targeting membrane lymphotoxin by means of a fusionprotein, monoclonal antibodies or genetic mutation inhibited therejection of intestinal allografts by CD8+ T cells. This effect wasassociated with decreased monokines induced by IFN-γ andsecondary-lymphoid-tissue chemokine-gene expression withinallografts and spleens, respectively. Blocking membrane lymphotoxin did not inhibit rejection mediated by CD4+ T cells.Combining disruption of membrane lymphotoxin and treatmentwith CTLA4−Ig inhibited rejection in wild-type mice.

Selected by Cezmi AkdisSwiss Institute of Allergy and Asthma Research, Davos, Switzerland


•• Histamine regulates T-cell and antibody responses bydifferential expression of H1 and H2 receptors. Jutel M,Watanabe T, Klunker S, Akdis M, Thomet OAR, Malolepszy J,Zak-Nejmark T, Koga R, Kobayashi T, Blaser K, Akdis CA:Nature 2001, 413:420-425.Significance: The finding that histamine receptors are present,regulated and functional on T cells has important implicationsfor therapeutic strategies in autoimmune, neoplastic and allergic diseases. This article describes a novel and importantregulatory loop in the control of inflammatory reactions.Findings: Histamine enhances Th1-type responses by triggeringthe histamine receptor type 1 (H1R), whereas both Th1- andTh2-type responses are negatively regulated by H2R because ofactivation of different biochemical intracellular signals. In mice,deletion of H1R results in suppression of IFN-γ and dominantsecretion of Th2 cytokines (IL-4 and IL-13). H2R-deleted miceshow upregulation of both Th1 and Th2 cytokines. Of relevanceto T-cell cytokine profiles, mice lacking H1R display increasedspecific-antibody response, with increased IgE and IgG1, IgG2band IgG3 in comparison with mice lacking H2R.

• Genetic engineering of a hypoallergenic trimer of themajor birch pollen allergen Bet v 1. Vrtala S, Hirtenlehner K,Susani M, Akdis M, Kussebi F, Akdis CA, Blaser K, Hufnagl P,Binder BR, Politou A et al.: FASEB J 2001, 11:2045-2047.Significance: Specific immunotherapy (SIT) is a common treat-ment for allergic diseases. Despite its usage in clinical practicefor nearly a century, more-rational and safer allergen preparations are required. Currently, one aim is to obtain bettervaccines by reducing IgE- and/or mast-cell-reactivity by allergen modification, while preserving T-cell responses. Thisstudy demonstrates that a strongly reduced allergenic activitycan be obtained by three covalently linked copies of the majorbirch-pollen allergen, Bet v 1, as a candidate vaccine for thetreatment of birch-pollen allergy.Findings: Stable recombinant (r) dimers and trimers of Bet v 1were generated by expressing two or three copies of theBet v 1 cDNA, linked by short oligonucleotide spacers with anopen reading frame, in Escherichia coli. Although the rBet v 1trimer contained specific IgE epitopes, it exhibited a 100-fold-reduced histamine and leukotriene release from basophils of birch-pollen-allergic patients, in comparison with the

rBet v 1 monomer. In contrast, the rBet v 1 trimer preservedT-cell reactivity and induced the release of Th1 cytokines morethan the rBet v 1 monomer.

• Overexpression of CD40 ligand in murine epidermis resultsin chronic skin inflammation and systemic autoimmunity.Mehling A, Loser K, Varga G, Metze D, Lugar TA, Schwarz T,Grabbe S, Beissert S: J Exp Med 2001, 194:615-628.Significance: Triggering of CD40 on dendritic cells orLangerhans cells (LCs) by CD40 ligand (CD40L)-expressingCD4+ T cells is a very strong activation signal, which is criticalboth for the T cells and the antigen-presenting cells. To investigate the effects of continuous activation of LCs of the skin, CD40L expression was targeted to the basal keratinocytes of the epidermis of mice.Findings: CD40L-keratinocyte-transgenic mice spontaneouslydeveloped dermatitis on the ears, face, tail and paws. Theyshowed increased LC migration to the dermis and massiveregional lymphadenopathy. In addition to chronic inflammatorydermatitis, mice developed autoantibodies, renal immunoglobulin deposits, proteinuria and lung fibrosis. These findingssuggest a systemic autoimmune disease, possibly by breakingimmune tolerance due to intensive LC activation via CD40.

• Allergic diathesis in transgenic mice with constitutiveT cell expression of inducible vasoactive intestinal peptidereceptor. Voice JK, Dorsam G, Lee H, Kong Y, Goetzl EJ:FASEB J 2001, 15:2489-2496.Significance: Vasoactive intestinal peptide (VIP), produced bycholinergic and sensory nerves and some immune-system cells,has potent effects on T-cell differentiation. The G-protein-coupled VIP receptor 1 (VPAC1 R) is constitutively expressedin T cells, whereas VPAC2 R is induced after stimulation of theTCR. Transgenic mice with constitutive T-cell expression of theinducible VIP receptor showed increased allergic reactions.Findings: Transgenic C57BL/6 mice that constitutively expressthe VPAC2 R selectively in CD4+ T cells developed increasedTh2 cytokines — IL-4 and IL-5 — and less IFN-γ after TCR activation. VPAC2-R-transgenic mice showed significantlyhigher IgE antibody responses as well as increased serum total IgE and IgG1, and blood eosinophilia. The same mice developed increased immediate-type hypersensitivity and suppressed delayed-type hypersensitivity responses in the skin.

Selected by Allison GreenCambridge Institute for Medical Research, Addenbrooke’s Hospital,

Cambridge, UKe-mail: [email protected]

•• Transgenic rescue implicates ββ2-microglobulin as a diabetes susceptibility gene in nonobese diabetic (NOD)mice. Hamilton-Williams EE, Serreze DV, Charlton B,Johnson EA, Marron MP, Müllbacher A, Slattery RM:Proc Natl Acad Sci USA 2001, 98:11533-11538.Significance: This paper provides important advances in defining genetic susceptibility to type 1diabetes in humans.Findings: Studies in NOD mice have suggested that a 24-centimorgan segment of chromosome 2 can imply diabetessusceptibility. One gene at this location encodes β2-microglobulin(β2M). By generating transgenic mice that expressed the

Paper alert 9

Allergy and hypersensitivity

Autoimmunity

‘a’ isoform of β2M from a non-diabetes-susceptible strain, theauthors showed that the presence of transgenic β2Ma restoredinsulitis and diabetes in NOD-β2M−/− mice. However, replace-ment of the ‘a’ isoform with the ‘b’ isoform of β2M from twoindependent diabetes-resistant strains of mice resulted inremarkably reduced diabetes susceptibility in comparison withmice carrying the ‘a’ isoform. Only 38% of the ‘b’ isoform micedeveloped insulitis whereas all β2Ma control mice developedsevere insulitis, suggesting that β2Ma confers susceptibility todisease at a very early age. Bone marrow chimeric studiesshowed that reconstitution of β2Mb mice with β2Ma bone marrow resulted in a low incidence of diabetes (30%) whereasreconstitution of β2Ma mice with bone marrow from β2Mb miceresulted in diabetes in 80% of reconstituted mice. Further,splenocytes from β2Mb→B2Ma mice could transfer diseaseinto NOD-SCID mice, whereas splenocytes from β2Ma→β2Mb

mice could not. Together these results indicate that the presence of the ‘a’ isoform of β2M in NOD mice exerts its diabetes-susceptibility function by altering nonhaematopoieticcells important for protection.

•• Defective T cell activation and autoimmune disorder inStra 13-deficient mice. Sun H, Lu B, Li R-Q, Flavell RA,Taneja R: Nat Immunol 2001, 2:1040-1047.Significance: This manuscript describes the importance of thetranscription repressor Stra 13 in the maintenance of T- and B-cellhomeostasis and peripheral tolerance in an aging immune system.Findings: Comparative FACS analysis of 2−3-month-old Stra13−/− and wild-type (WT) mice revealed no significant differences in T- or B-cell populations in lymphoid tissues.In vitro and in vivo functional assays, however, showed thatStra 13–/– T cells were less responsive to mitogenic and antigenic stimulation, and inefficiently differentiate into Th1 or Th2effector cells, due to defective IL-2 production. By 6−8 monthsof age, Stra 13−/− mice exhibited lymphoid-organ hyperplasia,and cellular infiltration of the lungs, kidneys and to a lesser

extent the liver, pancreas and heart. Expansion of germinal centers in the T-cell-rich regions of the spleen and lymph nodesoccurred, and thymic B-cell numbers increased. Stra 13−/−

mice developed autoantibodies to nuclear proteins andimmune-complex deposits in the kidney. These unregulatedB-cell responses were linked to defective FasL expression on CD4+ T cells in Stra 13−/− mice and, as a consequence, defective activation-induced cell death of B and T cells.

• Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis.McQualter JL, Darwiche R, Ewing C, Onuki M, Kay TW,Hamilton JA, Reid HH, Bernaud CCA: J Exp Med 2001,194:873-881.Significance: The authors provide evidence from murine models of multiple sclerosis that GM-CSF contributes to themaintenance of CNS lesions in multiple sclerosis. Furthermore,they show that treatment with anti-GM-CSF following onset ofdisease can promote rapid recovery without any relapse.Findings: NOD mice exhibit a relapsing/remitting experimentalautoimmune encephalitis (EAE) following immunization withmyelin oligodendrocyte glycoprotein (MOG), reminiscent of multiple sclerosis in humans. In contrast, NOD-GM-CSF−/− micedo not develop disease following immunization with MOG. Suchmice exhibited less-severe infiltrates in the CNS parenchymacompared with wild-type (WT) mice and, by 40 days post-immunization, infiltrates in NOD-GM-CSF−/− mice disappearedwhereas in WT mice they became more invasive. Functionalassays showed that T-cell but not B-cell responses to MOG wereimpaired in NOD-GM-CSF−/− mice compared with WT mice.Therapeutic administration of anti-GM-CSF to WT NOD mice atthe time of immunization only prevented disease if anti-GM-CSFwas continuously administered. In contrast, injection of anti-GM-CSF following the initiation of disease resulted in completerecovery. In both instances, similar injection of isotype-controlantibody did not prevent disease occurrence or progression.

10 Paper alert

Immunology

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