Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
Department of Pharmacology and Physiology, University of Rochester, Rochester, NY, USA.
Nat Immunol. 2022 Feb;23(2):287-302. doi: 10.1038/s41590-021-01105-x. Epub 2022 Feb 1.
The volume-regulated anion channel (VRAC) is formed by LRRC8 proteins and is responsible for the regulatory volume decrease (RVD) after hypotonic cell swelling. Besides chloride, VRAC transports other molecules, for example, immunomodulatory cyclic dinucleotides (CDNs) including 2'3'cGAMP. Here, we identify LRRC8C as a critical component of VRAC in T cells, where its deletion abolishes VRAC currents and RVD. T cells of Lrrc8c mice have increased cell cycle progression, proliferation, survival, Ca influx and cytokine production-a phenotype associated with downmodulation of p53 signaling. Mechanistically, LRRC8C mediates the transport of 2'3'cGAMP in T cells, resulting in STING and p53 activation. Inhibition of STING recapitulates the phenotype of LRRC8C-deficient T cells, whereas overexpression of p53 inhibits their enhanced T cell function. Lrrc8c mice have exacerbated T cell-dependent immune responses, including immunity to influenza A virus infection and experimental autoimmune encephalomyelitis. Our results identify cGAMP uptake through LRRC8C and STING-p53 signaling as a new inhibitory signaling pathway in T cells and adaptive immunity.
容积调节阴离子通道（VRAC）由 LRRC8 蛋白组成，负责细胞肿胀后调节性体积减少（RVD）。除了氯离子，VRAC 还运输其他分子，例如免疫调节环二核苷酸（CDNs），包括 2'3'cGAMP。在这里，我们确定 LRRC8C 是 T 细胞 VRAC 的关键组成部分，其缺失会消除 VRAC 电流和 RVD。Lrrc8c 小鼠的 T 细胞细胞周期进程、增殖、存活、Ca 内流和细胞因子产生增加——这种表型与 p53 信号转导下调有关。在机制上，LRRC8C 介导 2'3'cGAMP 在 T 细胞中的转运，导致 STING 和 p53 的激活。STING 的抑制可重现 LRRC8C 缺陷型 T 细胞的表型，而 p53 的过表达可抑制其增强的 T 细胞功能。Lrrc8c 小鼠的 T 细胞依赖性免疫反应加剧，包括对流感 A 病毒感染和实验性自身免疫性脑脊髓炎的免疫反应。我们的研究结果确定了通过 LRRC8C 和 STING-p53 信号转导摄取 cGAMP 作为 T 细胞和适应性免疫的新的抑制性信号通路。
