Thymocyte antigens do not induce tolerance in the CD4+T cell compartment

Thymocytes fail to tolerize the developing T cell repertoire to self MHC cl ass I (MHC I) Ags because transgenic (CD2K(b)) mice expressing H-2K(b) sole ly in lymphoid cell lineages reject skin grafts mismatched only for H-2K(b) . In this study, we examined why thymocytes fail to tolerize the T cell rep ertoire to self MHC I Ags. The ability of CD2K(b) mice to reject H-2K(b) sk in grafts was age dependent because CD2K(b) mice older than 20 wk accepted skin grafts. T cells from younger CD2K(b) mice proliferated, but did not de velop cytotoxic functions in vitro in response to H-2K(b). Proliferative re sponses were dominated by H-2K(b)-specific, CD4(+) T cells rather than CD8( +) T cells. Representative CD4(+) T cell clones from CD2K(b) mice were MHC II restricted and recognized processed H-2K(b). TCR transgenic mice were ge nerated from one CD4(+) T cell clone (361) to monitor development of H-2K(b )-specific immature thymocytes when all thymic cells or lymphoid cell linea ges only expressed H-2K(b). Thymocyte precursors were not eliminated and mi ce were not tolerant to H-2K(b) when Tg361 TCR transgenic mice:were intercr ossed with CD2K(b) mice. In contrast, all thymocyte precursors were elimina ted efficiently in thymic microenvironments in which all cells expressed H- 2K(b). We conclude that self MHC I Ags expressed exclusively in thymocytes do not induce T cell tolerance because presentation of processed self MHC I Ags on self MHC II molecules fails to induce negative selection of CD4(+) T cell precursors. This suggests that some self Ags are effectively compart mentalized and cannot induce self-tolerance in the T cell repertoire.