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

Thymocytes fail to tolerize the developing T cell repertoire to self MHC class I (MHC I) Ags because transgenic (CD2K^b) mice expressing H-2K^b solely 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 repertoire to self MHC I Ags. The ability of CD2K^b mice to reject H-2K^b skin 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 develop cytotoxic functions in vitro in response to H-2K^b. Proliferative responses 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 generated from one CD4⁺ T cell clone (361) to monitor development of H-2K^b-specific immature thymocytes when all thymic cells or lymphoid cell lineages only expressed H- 2K^b. Thymocyte precursors were not eliminated and mice were not tolerant to H-2K^b when Tg361 TCR transgenic mice were intercrossed with CD2K^b mice. In contrast, all thymocyte precursors were eliminated 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 compartmentalized and cannot induce self- tolerance in the T cell repertoire.