Birkner Katharina, Wasser Beatrice, Ruck Tobias, Thalman Carine, Luchtman Dirk, Pape Katrin, Schmaul Samantha, Bitar Lynn, Krämer-Albers Eva-Maria, Stroh Albrecht, Meuth Sven G, Zipp Frauke, Bittner Stefan
Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2, ), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Department of Neurology, University of Muenster, Muenster, Germany.
J Clin Invest. 2020 Feb 3;130(2):715-732. doi: 10.1172/JCI126381.
Although the impact of Th17 cells on autoimmunity is undisputable, their pathogenic effector mechanism is still enigmatic. We discovered soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex proteins in Th17 cells that enable a vesicular glutamate release pathway that induces local intracytoplasmic calcium release and subsequent damage in neurons. This pathway is glutamine dependent and triggered by binding of β1-integrin to vascular cell adhesion molecule 1 (VCAM-1) on neurons in the inflammatory context. Glutamate secretion could be blocked by inhibiting either glutaminase or KV1.3 channels, which are known to be linked to integrin expression and highly expressed on stimulated T cells. Although KV1.3 is not expressed in CNS tissue, intrathecal administration of a KV1.3 channel blocker or a glutaminase inhibitor ameliorated disability in experimental neuroinflammation. In humans, T cells from patients with multiple sclerosis secreted higher levels of glutamate, and cerebrospinal fluid glutamine levels were increased. Altogether, our findings demonstrate that β1-integrin- and KV1.3 channel-dependent signaling stimulates glutamate release from Th17 cells upon direct cell-cell contact between Th17 cells and neurons.
尽管Th17细胞对自身免疫的影响是无可争议的，但其致病效应机制仍然神秘莫测。我们在Th17细胞中发现了可溶性N - 乙基马来酰亚胺敏感因子附着受体（SNARE）复合蛋白，该蛋白促成了一种囊泡性谷氨酸释放途径，可诱导局部胞浆内钙释放并随后对神经元造成损伤。此途径依赖谷氨酰胺，并由炎症环境中β1整合素与神经元上的血管细胞黏附分子1（VCAM - 1）结合触发。抑制谷氨酰胺酶或KV1.3通道可阻断谷氨酸分泌，已知这两种物质与整合素表达相关且在活化的T细胞上高度表达。虽然KV1.3不在中枢神经系统组织中表达，但鞘内注射KV1.3通道阻滞剂或谷氨酰胺酶抑制剂可改善实验性神经炎症中的功能障碍。在人类中，多发性硬化症患者的T细胞分泌更高水平的谷氨酸，且脑脊液谷氨酰胺水平升高。总之，我们的研究结果表明，在Th17细胞与神经元直接细胞 - 细胞接触时，β1整合素和KV1.3通道依赖性信号传导刺激Th17细胞释放谷氨酸。
