Davidson, Anne

Abstract The development of systemic lupus erythematosus (SLE) is associated with overactivation of the type I interferon (IFN) pathway, lymphopenia, and increased follicular helper T (Tfh) cell differentiation. However, the cellular and molecular mechanisms of action of type I IFN in SLE remains incompletely understood. Here we show that type I IFN activates the mechanistic target of rapamycin complex 2 (mTORC2) in T cells to promote T cell lymphopenia. mTORC2 also promotes Tfh differentiation and disrupts Treg homeostasis. Inactivation of mTORC2 greatly ameliorated the immunopathology in a lupus-prone mouse model, associated with reduced Tfh differentiation, normalization of Treg homeostasis and reduced T cell glucose metabolism. These data indicate that mTORC2 acts downstream of type I IFN and costimulatory receptor ICOS, to promote T cell lymphopenia and Tfh differentiation in murine lupus development, suggesting that inhibition of mTORC2 could limit lupus disease progression. Supported by Lupus Research Alliance Mayo Foundation for Medical Education and Research R01AR077518

AbstractThe development of many systemic autoimmune diseases, including systemic lupus erythematosus, is associated with overactivation of the type I interferon (IFN) pathway, lymphopenia and increased follicular helper T (Tfh)‐cell differentiation. However, the cellular and molecular mechanisms underlying these immunological perturbations remain incompletely understood. Here, we show that the mechanistic target of rapamycin complex 2 (mTORC2) promotes Tfh differentiation and disrupts Treg homeostasis. Inactivation of mTORC2 in total T cells, but not in Tregs, greatly ameliorated the immunopathology in a systemic autoimmunity mouse model. This was associated with reduced Tfh differentiation, B‐cell activation, and reduced T‐cell glucose metabolism. Finally, we show that type I IFN can synergize with TCR ligation to activate mTORC2 in T cells, which partially contributes to T‐cell lymphopenia. These data indicate that mTORC2 may act as downstream of type I IFN, TCR and costimulatory receptor ICOS, to promote glucose metabolism, Tfh differentiation, and T‐cell lymphopenia, but not to suppress Treg function in systemic autoimmunity. Our results suggest that mTORC2 might be a rational target for systemic autoimmunity treatment.