mTORC2 contributes to systemic autoimmunity

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

来源：Immunology, 2023, 168(3): 554-568.

DOI：10.1111/imm.13594

• autoimmunity
• lupus
• SLE
• regulatory T cells
• T follicular helper cell

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.

• 单位
  哈尔滨医科大学; 河北医科大学