Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA; and.
Department of Molecular Imaging and Therapy, Beckman Research Institute of City of Hope, Duarte, CA.
J Immunol. 2022 Mar 15;208(6):1329-1340. doi: 10.4049/jimmunol.2100871. Epub 2022 Feb 25.
Activation of the Ca release-activated Ca (CRAC) channel is crucial for T cell functions. It was recently shown that naked cuticle homolog 2 (NKD2), a signaling adaptor molecule, orchestrates trafficking of ORAI1, a pore subunit of the CRAC channels, to the plasma membrane for sustained activation of the CRAC channels. However, the physiological role of sustained Ca entry via ORAI1 trafficking remains poorly understood. Using NKD2 as a molecular handle, we show that ORAI1 trafficking is crucial for sustained Ca entry and cytokine production, especially in inflammatory Th1 and Th17 cells. We find that murine T cells cultured under pathogenic Th17-polarizing conditions have higher Ca levels that are NKD2-dependent than those under nonpathogenic conditions. In vivo, deletion of alleviated clinical symptoms of experimental autoimmune encephalomyelitis in mice by selectively decreasing effector T cell responses in the CNS. Furthermore, we observed a strong correlation between NKD2 expression and proinflammatory cytokine production in effector T cells. Taken together, our findings suggest that the pathogenic effector T cell response demands sustained Ca entry supported by ORAI1 trafficking.
钙释放激活钙 (CRAC) 通道的激活对于 T 细胞功能至关重要。最近的研究表明，裸皮同源物 2 (NKD2)，一种信号衔接分子，协调 ORAI1（CRAC 通道的孔亚基）的运输到质膜，以持续激活 CRAC 通道。然而，通过 ORAI1 运输持续的 Ca 内流的生理作用仍知之甚少。使用 NKD2 作为分子把手，我们表明 ORAI1 运输对于持续的 Ca 内流和细胞因子产生至关重要，特别是在炎症性 Th1 和 Th17 细胞中。我们发现，在致病性 Th17 极化条件下培养的小鼠 T 细胞具有更高的 Ca 水平，这与非致病性条件下相比，依赖于 NKD2。在体内，通过选择性地减少中枢神经系统中的效应 T 细胞反应，减轻了实验性自身免疫性脑脊髓炎小鼠的临床症状。此外，我们观察到 NKD2 表达与效应 T 细胞中促炎细胞因子产生之间存在很强的相关性。总之，我们的发现表明，致病性效应 T 细胞反应需要 ORAI1 运输支持的持续 Ca 内流。
