Distinct PLZFCD8αα unconventional T cells enriched in liver use a cytotoxic mechanism to limit autoimmunity

Hepatic immune system is uniquely challenged to mount a controlled effector response to pathogens while maintaining tolerance to diet and microbial Ags. We have identified a novel population of innate-like, unconventional CD8ααTCRαβ T cells in naive mice and in human peripheral blood, called CD8αα T, capable of controlling effector T cell responses. They are NK1.1 (CD161 in human), express NK-inhibitory receptors, and express the promyelocytic leukemia zinc finger (PLZF) transcription factor that distinguishes them from conventional CD8 T cells. These cells display a cytotoxic phenotype and use a perforindependent mechanism to control Ag-induced or T cell-mediated autoimmune diseases. CD8αα T are dependent upon IL-15/IL-2Rβ signaling and PLZF for their development and/or survival. They are Foxp3-negative and their regulatory activity is associated with a functionally distinct Qa-1-dependent population coexpressing CD11c and CD244. A polyclonal TCR repertoire, an activated/memory phenotype, and the presence of CD8αα T in NKT- and in MAIT-deficient as well as in germ-free mice indicates that these cells recognize diverse self-protein Ags. Our studies reveal a distinct population of unconventional CD8 T cells within the natural immune repertoire capable of controlling autoimmunity and also providing a new target for therapeutic intervention.