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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)554-568
Number of pages15
Issue number3
StatePublished - Mar 2023


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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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