Interleukin-17A (IL-17A) is a major mediator of tissue inflammation in many autoimmune diseases. Anti-IL-17A is an effective treatment for psoriasis and is showing promise in clinical trials in multiple sclerosis. In this study, we find that IL-17A-defective mice or mice treated with anti-IL-17A at induction of experimental autoimmune encephalomyelitis (EAE) are resistant to disease and have defective priming of IL-17-secreting gd T (gdT17) cells and Th17 cells. However, T cells from Il17a À/À mice induce EAE in wild-type mice following in vitro culture with autoantigen, IL-1b, and IL-23. Furthermore, treatment with IL-1b or IL-17A at induction of EAE restores disease in Il17a À/À mice. Importantly, mobilization of IL-1b-producing neutrophils and inflammatory monocytes and activation of gdT17 cells is reduced in Il17a À/À mice. Our findings demonstrate that a key function of IL-17A in central nervous system (CNS) autoimmunity is to recruit IL-1b-secreting myeloid cells that prime pathogenic gdT17 and Th17 cells.

No abstract

No abstract

T cells are classically recognized as distinct subsets that express αβ or γδ TCRs. We identify a novel population of T cells that coexpress αβ and γδ TCRs in mice and humans. These hybrid αβ-γδ T cells arose in the murine fetal thymus by day 16 of ontogeny, underwent αβ TCR–mediated positive selection into CD4+ or CD8+ thymocytes, and constituted up to 10% of TCRδ+ cells in lymphoid organs. They expressed high levels of IL-1R1 and IL-23R and secreted IFN-γ, IL-17, and GM-CSF in response to canonically restricted peptide antigens or stimulation with IL-1β and IL-23. Hybrid αβ-γδ T cells were transcriptomically distinct from conventional γδ T cells and displayed a hyperinflammatory phenotype enriched for chemokine receptors and homing molecules that facilitate migration to sites of inflammation. These proinflammatory T cells promoted bacterial clearance after infection with Staphylococcus aureus and, by licensing encephalitogenic Th17 cells, played a key role in the development of autoimmune disease in the central nervous system.

Regulatory T (Treg) cells help to maintain tolerance and prevent the development of autoimmune diseases. Retinoic acid (RA) can promote peripheral conversion of naïve T cells into Foxp3+ Treg cells. Here, we show that RA can act as an adjuvant to induce antigen‐specific type 1 Treg (Tr1) cells, which is augmented by co‐administration of IL‐2. Immunization of mice with the model antigen KLH in the presence of RA and IL‐2 induces T cells that secrete IL‐10, but not IL‐17 or IFN‐γ, and express LAG‐3, CD49b and PD‐1 but not Foxp3, a phenotype typical of Tr1 cells. Furthermore, immunization of mice with the autoantigen MOG in the presence of RA and IL‐2 induces Tr1 cells, which suppress pathogenic Th1 and Th17 cells that mediate the development of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the CNS. Furthermore, immunization with a surrogate autoantigen, RA and IL‐2 prevents development of spontaneous autoimmune uveitis. Our findings demonstrate that the induction of autoantigen‐specific Tr1 cells can prevent the development of autoimmunity.