TRPM7 and magnesium orchestrate human CD4 T-cell activation and differentiation

T-lymphocyte activation is a crucial process in the regulation of innate and adaptive immune responses. The ion channel-kinase TRPM7, transient receptor potential cation channel subfamily M, member 7, has previously been implicated in cellular Mg²⁺ homeostasis, proliferation, and immune cell modulation. Here, we show that pharmacological and genetic silencing of TRPM7 leads to diminished activation and influences signaling pathways that guide human T_H17 or T_reg cell differentiation, following TCR-mediated stimulation. In primary human CD4 T cells and CRISPR-Cas9-engineered Jurkat T cells, inactivation or loss of TRPM7 led to distorted Mg²⁺ homeostasis and Ca²⁺ signaling, reduced NFAT translocation, decreased IL-2 secretion and altered T_H cell differentiation. While the activation of primary human CD4 T cells, as well as in vitro polarization into pro-inflammatory T_H17 cells was critically dependent on TRPM7, the polarization of naïve CD4 T cells into FOXP3⁺ regulatory T cells was not. Taken together, these results highlight TRPM7 as molecular switch in lymphocyte activation and polarization. Thus, suggesting a therapeutic potential for TRPM7 in numerous T-cell mediated diseases.