mTORC2 contributes to systemic autoimmunity.

Xian Zhou, Haiyu Qi, Meilu Li, Yanfeng Li, Xingxing Zhu, Shreyasee Amin, Mariam Alexander, Catherine Diadhiou, Anne Davidson, Hu Zeng

Immunology 2023 Mar

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The 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. © 2022 John Wiley & Sons Ltd.

Citation

Xian Zhou, Haiyu Qi, Meilu Li, Yanfeng Li, Xingxing Zhu, Shreyasee Amin, Mariam Alexander, Catherine Diadhiou, Anne Davidson, Hu Zeng. mTORC2 contributes to systemic autoimmunity. Immunology. 2023 Mar;168(3):554-568