Expansion and function of CD8⁺ T cells expressing Ly49 inhibitory receptors specific for MHC class I molecules

MHC class I-specific Ly49 inhibitory receptors regulate NK cell activation, thereby preventing autologous damage to normal cells. Ly49 receptors are also expressed on a subset of CD8⁺ T cells whose origin and function remain unknown. We report here that, despite their phenotypic and cytolytic similarities, Ly49⁺CD8⁺ T cells and conventional Ly49 ^-CD44^high memory-phenotype CD8⁺ T cells present strikingly distinct features. First, under steady state conditions Ly49 ⁺CD8⁺ T cells are poor cytokine producers (TNF-α and IFN-γ) upon TCR triggering. Second, Ly49⁺CD8⁺ T cells are not induced upon various settings of Ag immunization or microbial challenge. However, Ly49 can be induced on a fraction of self-specific CD8 ⁺ T cells if CD4⁺ T cells are present. Finally, the size of the Ly49⁺CD8⁺ T cell subset is selectively reduced in the absence of STAT1. These results indicate that Ly49 expression is associated with a differentiation program of cytolytic CD8⁺ T cells triggered upon chronic antigenic exposure. They further suggest that the size of the Ly49⁺CD8⁺ T cell subset marks a history of CD8⁺ T cell activation that might preferentially result from endogenous inducers of inflammation rather than from microbial infections.