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Self-Specific MHC Class II-Restricted CD4^-CD8^- T Cells That Escape Deletion and Lack Regulatory Activity¹

Section of Immunobiology, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520

In the presence of the I-E protein, transgenic (Tg) mice expressing the 1H3.1 TCR that is specific for the E52–68:I-A^b complex display drastic intrathymic deletion. Although peripheral T cells from these mice remained unresponsive to the E52–68:I-A^b complex, they contained a subpopulation able to specifically react to this complex in the presence of exogenous IL-2, indicating that some 1H3.1 TCR Tg T cells have escaped clonal deletion and efficiently populated the periphery. IL-2-dependent, E52–68:I-A^b complex-responsive T cells were CD4^-CD8^- and expressed the 1H3.1 TCR. Such T cells could develop intrathymically, did not show sign of regulatory/suppressor activity, displayed a typical naive phenotype, and seemed to persist in vivo over time. CD4^-CD8^- TCR Tg T cells were also detected when the surface density of the deleting ligand was increased on MHC class II⁺ cells. In addition, the development of CD4^-CD8^- 1H3.1 TCR Tg T cells could be supported by I-A^b molecules. These observations indicate that CD4 surface expression neither specifies, nor is required for, the thymic export of mature thymocytes expressing a MHC class II-restricted TCR. The data also show that, although the avidity of the interaction involved in intrathymic deletion is significantly lower than that involved in mature T cell activation, its range can be large enough to be influenced by the presence or absence of coreceptors. Finally, the margin created by the absence of CD4 coreceptor was substantial because it could accommodate various amounts of the deleting ligand on thymic stromal cells.

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