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Modulation of CD8⁺ T Cell Response to Antigen by the Levels of Self MHC Class I¹

Fabio R. Santori², Ivica Arsov^2,3 and Stanislav Vukmanovi⁴

Michael Heidelberger Division of Immunology, Department of Pathology, and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, NY 10016

The response of H-Y-specific TCR-transgenic CD8⁺ T cells to Ag is characterized by poor proliferation, cytolytic activity, and IFN- secretion. IFN- 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 responsiveness of transgenic CD8⁺ T cells cannot be ascribed to the epitope itself. Previously reported reactivity of this TCR to H-2A^b is also not the 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 molecules by breeding the mice to (C57BL/6 x B10.D2)F₁ or TAP1^+/- backgrounds partially restored cytotoxic activity and enhanced proliferative responses. These findings demonstrate that the self MHC class I gene dosage may regulate the extent of CD8⁺ T cell responsiveness to Ag.

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