MicroRNA-150 modulates intracellular Ca 2+ levels in naïve CD8+ T cells by targeting TMEM20

Abstract

Regulation of intracellular Ca²⁺ signaling is a major determinant of CD8⁺ T cell responsiveness, but the mechanisms underlying this regulation of Ca²⁺ levels, especially in naïve CD8⁺ T cells, are not fully defined. Here, we showed that microRNA-150 (miR-150) controls intracellular Ca²⁺ levels in naïve CD8⁺ T cells required for activation by suppressing TMEM20, a negative regulator of Ca²⁺ extrusion. miR-150 deficiency increased TMEM20 expression, which resulted in increased intracellular Ca²⁺ levels in naïve CD8⁺ T cells. The subsequent increase in Ca²⁺ levels induced expression of anergy-inducing genes, such as Cbl-b, Egr2, and p27, through activation of NFAT1, as well as reduced cell proliferation, cytokine production, and the antitumor activity of CD8⁺ T cells upon antigenic stimulation. The anergy-promoting molecular milieu and function induced by miR-150 deficiency were rescued by reinstatement of miR-150. Additionally, knockdown of TMEM20 in miR-150-deficient naïve CD8⁺ T cells reduced intracellular Ca²⁺ levels. Our findings revealed that miR-150 play essential roles in controlling intracellular Ca²⁺ level and activation in naïve CD8⁺ T cells, which suggest a mechanism to overcome anergy induction by the regulation of intracellular Ca²⁺ levels.