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 TH17 or Treg 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 TH cell differentiation. While the activation of primary human CD4 T cells, as well as in vitro polarization into pro-inflammatory TH17 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.