Modulation of CD8(+) T cell response to antigen by the levels of self MHC class I

The response of H-Y-specific TCR-transgenic CD8(+) T cells to Ag is charact erized by poor proliferation, cytolytic activity, and IFN-gamma secretion. IFN-gamma secretion, but not cytotoxic function, can be rescued by the B7.1 molecule, suggesting that costimulation can selectively enhance some, but not all, effector CD8(+) T cell responses. Although the H-Y epitope binds H -2D(b) relatively less well than some other epitopes, it can induce potent CTL responses in nontransgenic mice, suggesting that the observed poor resp onsiveness of transgenic CD8(+) T cells cannot be ascribed to the epitope i tself. Previously reported reactivity of this TCR to H-2A(b) is also not th e cause of the poor responsiveness of the H-Y-specific CD8(+) T cells, as H -Y-specific CD8(+) T cells obtained from genetic backgrounds lacking H-2A(b ) also responded poorly. Rather, reducing the levels of H-2(b) class I mole cules by breeding the mice to (C57BL/6 X B10.D2)F-1, or TAP1(+/-) backgroun ds partially restored cytotoxic activity and enhanced proliferative respons es. These findings demonstrate that the self MHC class I gene dosage may re gulate the extent of CD8(+) T cell responsiveness to Ag.