TRPM7 activity drives human CD4 T-cell activation and differentiation in a magnesium dependent manner
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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 2+ 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 2+ homeostasis, Ca 2+ 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 reg ) was not. Taken together, these results highlight TRPM7 as a key protein of cellular Mg 2+ homeostasis and CD4 T-cell activation. Its role in lymphocyte activation suggests therapeutic potential for TRPM7 in numerous T-cell mediated diseases.
Summary
TRPM7 is crucial to maintaining cellular Mg 2+ homeostasis and regulates human CD4 T-cell activation by modulating early Ca 2+ signaling events in response to TCR-mediated stimulation subsequently, influencing T-cell differentiation in a Mg 2+ dependent manner.
