Restricted MHC–peptide repertoire predisposes to autoimmunity

Logunova, Nadezda N.; Viret, Christophe; Pobezinsky, Leonid A; Miller, Sara A.; Kazansky, Dmitry; Sundberg, John P.; Chervonsky, Alexander V.

doi:10.1084/jem.20050198

Cited by 31 publications

(30 citation statements)

References 54 publications

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“…Some T cell clones were in fact demonstrated to show specificity to both classes of MHC molecules (41)(42)(43)(44)(45)(46)(47). When positively selected, those cells with TCRs of dual class specificity should tend to differentiate into CD4 ϩ T cells rather than CD8 ϩ T cells, as observed in the present study.…”

Section: Positive Selection In the Presence Of Both Classes Of Selectsupporting

confidence: 53%

“…However, these mechanisms, in addition to other mechanisms (25, 39), could underlie the higher proportion of CD4 ϩ T cells than CD8 ϩ T cells in normal animals of normal conditions. It is also possible that these mechanisms may contribute to explain the influence of class II MHC on the differentiation of some pathogenic CD8 ϩ T cells (42,43), as recently suggested by Logunova et al (44).…”

Section: Positive Selection In the Presence Of Both Classes Of Selectmentioning

confidence: 77%

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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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Section: Positive Selection In the Presence Of Both Classes Of Selectsupporting

confidence: 53%

Section: Positive Selection In the Presence Of Both Classes Of Selectmentioning

confidence: 77%

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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“…Recent studies suggest that, when only a limited set of self-pMHC complexes is available in the thymus for positive selection, the TCRs of the selected mature T cells are especially degenerate and tend to recognize both MHC class I and MHC class II as well as multiple foreign (allogeneic) MHC (38,39). The 2C TCR arose in a BALB.B (H2 b ) mouse (10,11).…”

Section: Discussionmentioning

confidence: 99%

Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Holler

Mahajan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Most ␣␤ T cells belong to one of the two lineages defined by the mutually exclusive expression of CD8 or CD4 coreceptors, which bind MHC class I and class II molecules, respectively. Because the binding of the coreceptors to MHC molecules stabilizes weak interactions between TCRs and peptide-MHC (pMHC) complexes, CD8 ϩ T cells are MHC class I-restricted whereas CD4 ϩ T cells are MHC class II-restricted. The concordance of CD4 or CD8 lineage development with specificity for class I or II MHC is established during differentiation of CD4 ϩ CD8 ϩ double-positive (DP) thymocytes in the thymus by a process referred to as positive selection (4). Whether a DP thymocyte differentiates into a CD4 ϩ or CD8 ϩ T cell depends on differences in TCR signaling as a result of interactions among TCR, coreceptors, and self-peptide-MHC (self-pMHC) complexes (5-8).Many TCRs are known to interact not only with self-but also with foreign MHC molecules (alloreactivity). Among the bestdocumented examples is the recognition of different pMHC complexes by a TCR called 2C (9). The 2C TCR was derived from a CD8 ϩ cytotoxic T lymphocyte (CTL) clone from an H-2 b mouse (BALB.B) that was injected with H-2 d cells (10, 11). The 2C TCR reacts with L d in association with two overlapping peptides QL-SPFPFDL (QL9) and p2Ca derived from ␣-ketoglutarate dehydrogenase (10,12,13). The 2C TCR is also alloreactive to K bm3 in association with the dEV8 peptide derived from NADHubiquinone oxoreductase (14,15). By constructing transgenic mice expressing the 2C TCR and crossing the TCR transgene onto different H-2 backgrounds, it was shown that the positive selecting MHC for the 2C T cells is K b (16,17). Among the naturally derived peptides recognized by the 2C TCR in association with L d and K bm3 , p2Ca and dEV8 bind weakly to K b and behave as weak agonists (18). However, several strong agonist peptides have been identified in combinatorial libraries to associate with K b and activate the 2C T cells (19). Among them, SIYRYYGL (SIY) has been extensively characterized. In addition to recognizing various peptides in association with MHC class I L d , K bm3 , and K b molecules, the 2C TCR was also shown recently to recognize a nonclassical class I molecule, leading to differentiation of CD8 ϩ T cells that home to the intestine during fetal and neonatal development (20).The ability of a given TCR to interact with multiple MHC molecules, especially both class I and class II, can have a significant influence on the development of CD4 versus CD8 T cells. For example, the HY TCR nominally recognizes class I D b for CD8 T cell development but also interacts with class II I-A b for CD4 T cell development (21). Similarly, the HA and AND TCRs nominally interact with class II MHC for CD4 T cell development but also promote the development of CD8 T cells on either the RAG Ϫ/Ϫ or the CD4 Ϫ/Ϫ plus TCR␣ Ϫ/Ϫ background (22, 23). The development of CD8 HA or AND transgenic T cells was shown to require the interaction of the TCRs with both class I and class II MHC molecules....

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“…bare, the disease was given the name bare lymphocyte syndrome. By synchronizing the innate and adaptive immune network, these MHC proteins help to distinguish self from non-self peptides [3], control autoimmunity [4,5] and wage war against the invaders [6]. The loss of these antigen ferrying molecules in BLS results in a fragile immune system very much resembling the severe combined immunodeficiency syndrome (SCID) [1,7,8].…”

Section: Introductionmentioning

confidence: 99%

Bare lymphocyte syndrome: An opportunity to discover our immune system

2012

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Restricted MHC–peptide repertoire predisposes to autoimmunity

Cited by 31 publications

References 54 publications

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

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

Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Bare lymphocyte syndrome: An opportunity to discover our immune system

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Restricted MHC–peptide repertoire predisposes to autoimmunity

Cited by 31 publications

References 54 publications

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

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

Development of CD4+T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms

Bare lymphocyte syndrome: An opportunity to discover our immune system

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Development of CD4⁺T cells expressing a nominally MHC class I-restricted T cell receptor by two different mechanisms