The murine bm12 gene conversion provides evidence that T cells recognize predominantly Ia conformation.

Tse, Harley Y.; Kanamori, Shuichi; Walsh, William; Hansen, Ted H.

doi:10.1073/pnas.82.20.7058

Cited by 19 publications

(10 citation statements)

References 30 publications

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“…Moreover, body weight gain associated with serositis (e.g., ascites) and lymphoid organomegaly phenomena common in the cGvHD-induced model (30, 38) were also statistically increased in CD6 −/− mice (Figure 5B). The assessment of splenomegaly at the end of the follow-up period (week 5) showed, however, statistically significant lower total spleen cell numbers (Figure 5C, left) and spleen weight (Figure 5C, right) in CD6 −/− mice compared with their CD6 +/+ counterparts.…”

Section: Resultsmentioning

confidence: 89%

Relevance of CD6-Mediated Interactions in the Regulation of Peripheral T-Cell Responses and Tolerance

Consuegra-Fernández¹,

Martínez-Florensa²,

Aranda³

et al. 2017

Front. Immunol.

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The CD6 lymphocyte receptor has been involved in the pathophysiology of different autoimmune disorders and is now considered a feasible target for their treatment. In vitro data show the relevance of CD6 in the stabilization of adhesive contacts between T-cell and antigen-presenting cells, and the modulation of T-cell receptor signals. However, the in vivo consequences of such a function are yet undisclosed due to the lack of suitable genetically modified animal models. Here, the in vitro and in vivo challenge of CD6-deficient (CD6−/−) cells with allogeneic cells was used as an approach to explore the role of CD6 in immune responses under relative physiological stimulatory conditions. Mixed lymphocyte reaction (MLR) assays showed lower proliferative responses of splenocytes from CD6−/− mice together with higher induction of regulatory T cells (Treg, CD4+CD25+FoxP3+) with low suppressive activity on T and B-cell proliferation. In line with these results, CD6−/− mice undergoing a lupus-like disorder induced by chronic graft-versus-host disease (cGvHD) showed higher serum titers of anti-double-stranded DNA and nucleosome autoantibodies. This occurred together with reduced splenomegaly, which was associated with lower in vivo bromodesoxyuridine incorporation of spleen cells and with increased percentages of spleen follicular B cells (B2, CD21+CD23hi) and Treg cells. Interestingly, functional analysis of in vivo-generated CD6−/− Treg cells exhibited defective suppressive activity. In conclusion, the data from MLR and cGvHD-induced lupus-like models in CD6−/− mice illustrate the relevance of CD6 in T (and B) cell proliferative responses and, even more importantly, Treg induction and suppressive function in the in vivo maintenance of peripheral tolerance.

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Section: Resultsmentioning

confidence: 89%

Relevance of CD6-Mediated Interactions in the Regulation of Peripheral T-Cell Responses and Tolerance

Consuegra-Fernández¹,

Martínez-Florensa²,

Aranda³

et al. 2017

Front. Immunol.

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“…Nevertheless, any theory must explain the high frequency of alloreactivity to mutant H-2 molecules, which in some cases differ from the wild-type protein by only a few amino acids. It has been speculated that MHC-encoded glycoproteins contain many epitopes for T cell recognition and that these are highly dependent T CELL RECEPTOR REPERTOIRE TO I-At-`z on three-dimensional structure (12) . Thus, even a small change in amino acid sequence could alter the three-dimensional structure and result in many new epitopes .…”

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confidence: 99%

Molecular genetic analysis of 178 I-Abm12-reactive T cells.

Bill

Yagüe

Appel

et al. 1989

The Journal of Experimental Medicine

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We have studied the genetic diversity of the TCR repertoire to the murine alloantigen I-Abm12 by generating a panel of 178 C57BL/10-derived I-Abm12-reactive T cell hybridomas. The expression of V alpha and V beta gene families was examined in this panel and the frequency of expression of V beta, but not ofV alpha, gene families differed significantly from that observed in a companion panel of random C57BL/10-derived hybridomas. The V beta 5 gene family was expressed significantly less frequently while the V beta 14, V beta 15, and V beta 16 genes were expressed significantly more frequently in the panel of I-Abm12-reactive than in the panel of random hybridomas. The junctional regions (VJ alpha and VDJ beta) of TCR V alpha and V beta genes from selected I-Abm12-specific hybridomas were amplified using the polymerase chain reaction, and directly sequenced. Surprisingly, no conserved J alpha, D beta, J beta, or N region-encoded sequences among these selected I-Abm12-reactive TCRs were identified. Thus, the T cell response to an I-A alloantigen that differs by only three amino acid residues from the I-A molecule of the responding strain is genetically complex but nonrandom. We have estimated that the repertoire to this alloantigen is comprised of at least 37 different TCRs.

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“…T he injection of spleen cells from bm12 mice into C57BL/6 recipients induces a chronic graft-vs-host (cGVH) 3 reaction characterized by systemic autoimmunity similar to that seen in systemic lupus erythematosus (1,2). The cGVH reaction is driven by MHC class II recognition.…”

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confidence: 99%

“…The cGVH reaction is driven by MHC class II recognition. In this cGVH model, the recipient strain (B6) differs from the donor B6.C-H2 bm12 /KhEg (bm12) by only 3 aa in the ␤-chain of MHC class II molecule I-A (3,4). The autoreactivity is a result of recognition of recipient B cell MHC class II by donor T cells (5).…”

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confidence: 99%

The Mer Receptor Tyrosine Kinase Is Required for the Loss of B Cell Tolerance in the Chronic Graft-versus-Host Disease Model of Systemic Lupus Erythematosus

Shao

Eisenberg

Cohen

2008

The Journal of Immunology

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The Mer receptor tyrosine kinase mediates apoptotic cell phagocytosis and modulates macrophage cytokine production. Mer−/− mice have defective clearance of apoptotic debris and develop a systemic lupus erythematosus-like autoimmune syndrome. It was surprising then that B6-Mer−/− recipients of bm12 spleen cells failed to develop anti-dsDNA and anti-chromatin autoantibodies, whereas B6 hosts produced the expected autoimmune chronic graft-vs-host (cGVH) reaction. The lack of autoantibody formation in cGVH was not due to the failure of Mer-deficient hosts to provoke alloreactivity, because Mer−/− spleen cells were recognized by bm12 T cells in MLR. Cell transfer experiments in Rag-knockout mice indicated that the lack of autoantibody production in Mer−/− cGVH disease hosts was due to an intrinsic B cell defect. This defect did not cause a global inability to produce autoantibodies, because in vivo exposure to LPS stimulated production of autoantibodies in both B6 and Mer−/− mice. We further observed that wild-type B6 B cells up-regulated Mer upon activation in cGVH, and that B cells from mice lacking Mer showed a decreased up-regulation of activation-associated cell surface markers. These findings indicate that Mer serves an important role in the activation of self-reactive B cells in systemic autoimmunity.

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The murine bm12 gene conversion provides evidence that T cells recognize predominantly Ia conformation.

Cited by 19 publications

References 30 publications

Relevance of CD6-Mediated Interactions in the Regulation of Peripheral T-Cell Responses and Tolerance

Relevance of CD6-Mediated Interactions in the Regulation of Peripheral T-Cell Responses and Tolerance

Molecular genetic analysis of 178 I-Abm12-reactive T cells.

The Mer Receptor Tyrosine Kinase Is Required for the Loss of B Cell Tolerance in the Chronic Graft-versus-Host Disease Model of Systemic Lupus Erythematosus

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