Hoelting Kilian, Madlmayr Anna, Hoeger Birgit, Lewitz Dorothea, Weng Marius, Haider Tanja, Duggan Michelle, Ross Rylee, Horgen F David, Sperandio Markus, Dietrich Alexander, Gudermann Thomas, Zierler Susanna
Walther Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München, Goethestr.33, 80336 Munich, Germany.
Institute of Pharmacology, Johannes Kepler University Linz, Altenbergerstr. 69, 4040 Linz, Austria.
bioRxiv. 2024 Dec 7:2024.12.04.626765. doi: 10.1101/2024.12.04.626765.
T lymphocyte activation is a crucial process in the regulation of innate and adaptive immune responses. The ion channel-kinase TRPM7 has previously been implicated in cellular Mg homeostasis, proliferation, and immune cell modulation. Here, we show that pharmacological and genetic silencing of TRPM7 leads to diminished human CD4 T-cell activation and proliferation following TCR mediated stimulation. In both primary human CD4 T cells and CRISPR/Cas-9 engineered Jurkat T cells, loss of TRPM7 led to altered Mg homeostasis, Ca signaling, reduced NFAT translocation, decreased IL-2 secretion and ultimately diminished proliferation and differentiation. While the activation of primary human CD4 T cells was dependent on TRPM7, polarization of naïve CD4 T cells into regulatory T cells (T) was not. Taken together, these results highlight TRPM7 as a key protein of cellular Mg homeostasis and CD4 T-cell activation. Its role in lymphocyte activation suggests therapeutic potential for TRPM7 in numerous T-cell mediated diseases.
T淋巴细胞活化是先天免疫和适应性免疫反应调节中的一个关键过程。离子通道激酶TRPM7先前已被证明与细胞镁稳态、增殖和免疫细胞调节有关。在此，我们表明，TRPM7的药理学沉默和基因沉默会导致TCR介导的刺激后人类CD4 T细胞活化和增殖减少。在原代人类CD4 T细胞和CRISPR/Cas-9工程化的Jurkat T细胞中，TRPM7的缺失均导致镁稳态改变、钙信号传导、NFAT易位减少、IL-2分泌降低，并最终导致增殖和分化减少。虽然原代人类CD4 T细胞的活化依赖于TRPM7，但初始CD4 T细胞向调节性T细胞（Treg）的极化则不依赖于TRPM7。综上所述，这些结果突出了TRPM7作为细胞镁稳态和CD4 T细胞活化的关键蛋白。其在淋巴细胞活化中的作用表明TRPM7在众多T细胞介导的疾病中具有治疗潜力。
