Distinct PLZF ⁺CD8αα ⁺ unconventional T cells enriched in liver use cytotoxic mechanism to limit autoimmunity ¹

Abstract

Hepatic immune system is uniquely challenged to mount a controlled effector response to pathogens while maintaining tolerance to diet and microbial antigens. We have identified a novel population of innate-like, unconventional CD8αα ⁺TCRαβ ⁺ T cells in naïve mice and in human peripheral blood, called CD8αα T _unc, 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 perforin dependent mechanism to control antigen-induced or T cell-mediated autoimmune diseases. CD8αα T _unc 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 ^b-dependent population co-expressing CD11c and CD244. A polyclonal TCR repertoire, an activated/memory phenotype and the presence of CD8αα T _unc in NKT- and in MAIT-deficient, as well as in germ-free mice indicates that these cells recognize diverse self-protein antigens. 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.