Negative feedback control of autoimmunity by a novel population of regulatory unconventional CD8+ T cells

Abstract

Abstract Immune tolerance mediated by regulatory T cells is important in the control of homeostasis. The characterization of regulatory CD8 T cells has been hampered by inability to distinguish them from conventional CD8 T cells. We have identified a novel population of unconventional cytotoxic TCRαβ+CD8+ T cells with regulatory properties, called uTr, in both naïve mice and humans. The uTr cells are innate-like, express the promyelocytic leukemia zinc finger (PLZF) transcription factor and display an activated-memory phenotype (CD122high, CD44high,CD62Llow, CD69+). They are CD8αα+, NK1.1+(CD161+ in human), express NK inhibitory receptors and are dependent upon IL-15/IL-2Rβ signaling. A significant decrease in the frequency of uTr cells in PLZF−/− mice suggests their dependency on PLZF expression. Similarly, a significant reduction of uTr cells in Qa-1b−/− mice indicates that a sizable proportion of them are restricted by Qa-1b MHC molecules. The deep-sequencing, RT-PCR and FACS analysis of sorted hepatic uTr cells indicate a polyclonal TCR repertoire in both mice and humans. Adoptive transfer of sorted hepatic uTr cells but not conventional CD8 T cells protects B6 mice from EAE as well as RAG1−/− mice from T cell-induced colitis. The uTr cells secrete IFNγ, IL-4 and IL-17 but not TGFβ and express perforin and granzyme B and the mechanism(s) of regulation is dependent upon perforin. The uTr cells are distinct from other unconventional T cells, including NKT cells, NKT-dependent innate-like CD8 T and MAIT cells. Collectively, we have identified a novel unconventional regulatory CD8 T cells that are involved in a negative feedback mechanism of regulation of autoimmunity and also have important implications for anti-cancer immunity.