Division of Rheumatology, Department of Medicine, Mayo Clinic Rochester, Minnesota, USA.
Department of Rheumatology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
Immunology. 2023 Mar;168(3):554-568. doi: 10.1111/imm.13594. Epub 2022 Nov 2.
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.
许多系统性自身免疫性疾病的发展，包括红斑狼疮，与 I 型干扰素（IFN）途径的过度激活、淋巴细胞减少和滤泡辅助 T（Tfh）细胞分化增加有关。然而，这些免疫失调的细胞和分子机制仍不完全清楚。在这里，我们表明雷帕霉素复合物 2（mTORC2）的机械靶点促进 Tfh 分化并破坏 Treg 稳态。在全身性自身免疫小鼠模型中，在总 T 细胞中但不在 Tregs 中失活 mTORC2 极大地改善了免疫病理学。这与 Tfh 分化、B 细胞激活和 T 细胞葡萄糖代谢减少有关。最后，我们表明 I 型 IFN 可以与 TCR 交联协同激活 T 细胞中的 mTORC2，这部分有助于 T 细胞淋巴细胞减少。这些数据表明，mTORC2 可能作为 I 型 IFN、TCR 和共刺激受体 ICOS 的下游，促进葡萄糖代谢、Tfh 分化和 T 细胞淋巴细胞减少，但不抑制系统性自身免疫中的 Treg 功能。我们的结果表明，mTORC2 可能是系统性自身免疫治疗的合理靶点。
