Preferential expression of TCR Vα regions in CD4/CD8 subsets: class discrimination or co-receptor recognition?

Sim, Bee-Cheng; Lo, David; Gascoigne, Nicholas R. J.

doi:10.1016/s0167-5699(98)01257-2

Cited by 48 publications

(31 citation statements)

References 36 publications

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“…TCR ␣-chain interactions have been shown to dominate the interface between the TCR and pMHC in many complexes (23), and recent evidence suggests that they are important in maintaining the roughly conserved docking orientation (37). In addition, V␣ genes have been reported to play a major role in determining whether T cells are MHC class I or class II restricted (38,39). Our data indicate that V␣ genes are also critical in determining MHC restriction between different class I alleles.…”

Section: Discussionmentioning

confidence: 51%

TCRα Genes Direct MHC Restriction in the Potent Human T Cell Response to a Class I-Bound Viral Epitope

Miles

Borg

Brennan

et al. 2006

The Journal of Immunology

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The underlying generic properties of αβ TCRs that control MHC restriction remain largely unresolved. To investigate MHC restriction, we have examined the CTL response to a viral epitope that binds promiscuously to two human leukocyte Ags (HLAs) that differ by a single amino acid at position 156. Individuals expressing either HLA-B*3501 (156Leucine) or HLA-B*3508 (156Arginine) showed a potent CTL response to the 407HPVGEADYFEY417 epitope from EBV. Interestingly, the response was characterized by highly restricted TCR β-chain usage in both HLA-B*3501+ and HLA-B*3508+ individuals; however, this conserved TRBV9+ β-chain was associated with distinct TCR α-chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR α-chain usage determined the HLA restriction of the CTLs. Structural studies revealed significant differences in the mobility of the peptide when bound to HLA-B*3501 or HLA-B*3508. In HLA-B*3501, the bulged section of the peptide was disordered, whereas in HLA-B*3508 the bulged epitope adopted an ordered conformation. Collectively, these data demonstrate not only that mobile MHC-bound peptides can be highly immunogenic but can also stimulate an extremely biased TCR repertoire. In addition, TCR α-chain usage is shown to play a critical role in controlling MHC restriction between closely related allomorphs.

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Section: Discussionmentioning

confidence: 51%

TCRα Genes Direct MHC Restriction in the Potent Human T Cell Response to a Class I-Bound Viral Epitope

Miles

Borg

Brennan

et al. 2006

The Journal of Immunology

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“…Our observations further indicate that small, germlineencoded molecular changes distal to the antigen-binding site of the TCR can have profound effects on the developmental biology of individual clonotypes. Since some of the molecular differences that are associated with avidity maturation of the IGRP 206-214 -reactive T cell population map to the CDR1α, and since some CDR1α residues (i.e., position 27) interact directly with MHC molecules (34)(35)(36), it is possible that the above differences in biophysical, functional, and developmental behavior are determined by differences in the strength with which these TCRs engage MHC molecules in the absence of cognate peptide ligand. In support of this hypothesis, we have observed that, unlike Vα17.4 + CTLs, Vα17.5 + CTLs can kill TUM-pulsed RMA-S-K d cells and can produce substantial amounts of IFN-γ in response to TUM-pulsed dendritic cells (our unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Developmental control of CD8+ T cell–avidity maturation in autoimmune diabetes

Han¹,

Serra²,

Yamanouchi³

et al. 2005

J. Clin. Invest.

100

108

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The progression of immune responses is generally associated with an increase in the overall avidity of antigenspecific T cell populations for peptide-MHC. This is thought to result from preferential expansion of high-avidity clonotypes at the expense of their low-avidity counterparts. Since T cell antigen-receptor genes do not mutate, it is puzzling that high-avidity clonotypes do not predominate from the outset. Here we provide a developmental basis for this phenomenon in the context of autoimmunity. We have carried out comprehensive studies of the diabetogenic CD8 + T cell population that targets residues 206-214 of the β cell antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP 206-214 ) and undergoes avidity maturation as disease progresses. We find that the succession of IGRP 206-214 -specific clonotypes with increasing avidities during the progression of islet inflammation to overt diabetes in nonobese diabetic mice is fueled by autoimmune inflammation but opposed by systemic tolerance. As expected, naive high-avidity IGRP 206-214 -specific T cells respond more efficiently to antigen and are significantly more diabetogenic than their intermediate-or low-avidity counterparts. However, central and peripheral tolerance selectively limit the contribution of these high-avidity T cells to the earliest stages of disease without abrogating their ability to progressively accumulate in inflamed islets and kill β cells. These results illustrate the way in which incomplete deletion of autoreactive T cell populations of relatively high avidity can contribute to the development of pathogenic autoimmunity in the periphery. IntroductionThe diversity of the preimmune T and B cell repertoires is accomplished by random rearrangement of large arrays of V, D, and J genes during lymphocyte development. The encoded molecules fold into structures in which 6 hypervariable complementarity-determining regions (CDRs) are brought together to form the receptors' antigen-binding site (1, 2). A key common feature of the antigen-binding site of these receptors is its conformational flexibility, which affords ligand promiscuity (1-11). This degeneracy in antigen recognition is typically associated with low-affinity interactions and is a hallmark of the preimmune B lymphocyte repertoire. It is via the processes of somatic mutation of B cell receptors and selection of antigen-reactivated B cells within germinal centers that B cell responses improve in both their affinity and fidelity for antigen recognition (12-16). This transition is paralleled by dramatic increases in both the association rate of the antigen-binding reaction and the structural rigidity of the receptors' antigen-binding site (9,17).T cell responses usually undergo an analogous process of avidity maturation. Although there is some controversy as to the underlying kinetic mechanisms (i.e., avidity maturation proceeding through or only up to certain avidity thresholds), most studies concur that this process results from competitive survival of c...

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“…Thus, it is quite likely that class I and class II MHC molecules actually look alike to TCR. In fact, there are no critical (although some) differences in V␣/V␤ usage between class I MHC-restricted and class II MHC-restricted TCRs (39,40). If this is the case, the coreceptor may well primarily determine the class restriction.…”

Section: The Interaction Of a Single Tcr With Multiple Mhc Upon Thymimentioning

confidence: 99%

Cross-Positive Selection of Thymocytes Expressing a Single TCR by Multiple Major Histocompatibility Complex Molecules of Both Classes: Implications for CD4+ versus CD8+ Lineage Commitment

Eshima

Suzuki

Shinohara

2006

The Journal of Immunology

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This study has investigated the cross-reactivity upon thymic selection of thymocytes expressing transgenic TCR derived from a murine CD8+ CTL clone. The Idhigh+ cells in this transgenic mouse had been previously shown to mature through positive selection by class I MHC, Dq or Lq molecule. By investigating on various strains, we found that the transgenic TCR cross-reacts with three different MHCs, resulting in positive or negative selection. Interestingly, in the TCR-transgenic mice of H-2q background, mature Idhigh+ T cells appeared among both CD4+ and CD8+ subsets in periphery, even in the absence of RAG-2 gene. When examined on β2-microglobulin−/− background, CD4+, but not CD8+, Idhigh+ T cells developed, suggesting that maturation of CD8+ and CD4+ Idhigh+ cells was MHC class I (Dq/Lq) and class II (I-Aq) dependent, respectively. These results indicated that this TCR-transgenic mouse of H-2q background contains both classes of selecting MHC ligands for the transgenic TCR simultaneously. Further genetic analyses altering the gene dosage and combinations of selecting MHCs suggested novel asymmetric effects of class I and class II MHC on the positive selection of thymocytes. Implications of these observations in CD4+/CD8+ lineage commitment are discussed.

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Preferential expression of TCR Vα regions in CD4/CD8 subsets: class discrimination or co-receptor recognition?

Cited by 48 publications

References 36 publications

TCRα Genes Direct MHC Restriction in the Potent Human T Cell Response to a Class I-Bound Viral Epitope

TCRα Genes Direct MHC Restriction in the Potent Human T Cell Response to a Class I-Bound Viral Epitope

Developmental control of CD8+ T cell–avidity maturation in autoimmune diabetes

Cross-Positive Selection of Thymocytes Expressing a Single TCR by Multiple Major Histocompatibility Complex Molecules of Both Classes: Implications for CD4+ versus CD8+ Lineage Commitment

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