Inactivation of TRPM7 Kinase in Mice Results in Enlarged Spleens, Reduced T-cell Proliferation and Diminished Store-operated Calcium Entry

T lymphocytes enlarge (blast) and proliferate in response to antigens in a multistep program that involves obligatory cytosolic calcium elevations. Store-operated calcium entry (SOCE) pathway is the primary source of Ca in these cells. Here, we describe a novel modulator of blastogenesis, proliferation and SOCE: the TRPM7 channel kinase. TRPM7 kinase-dead (KD) K1646R knock-in mice exhibited splenomegaly and impaired blastogenic responses elicited by PMA/ionomycin or anti-CD3/CD28 antibodies. Splenic T-cell proliferation in vitro was weaker in the mutant compared to wildtype littermates. TRPM7 current magnitudes in WT and KD mouse T cells were, however, similar. We tested the dependence of T-cell proliferation on external Ca and Mg concentrations. At a fixed [Mg] of ~0.4 mM, Ca stimulated proliferation with a steep concentration dependence and vice versa, at a fixed [Ca] of ~0.4 mM, Mg positively regulated proliferation but with a shallower dependence. Proliferation was significantly lower in KD mouse than in wildtype at all Ca and Mg concentrations. Ca elevations elicited by anti-CD3 antibody were diminished in KD mutant T cells and SOCE measured in activated KD splenocytes was reduced. These results demonstrate that a functional TRPM7 kinase supports robust SOCE, blastogenesis and proliferation, whereas its inactivation suppresses these cellular events.