TMEM41B is an endoplasmic reticulum Ca2+ release channel maintaining naive T cell quiescence and responsiveness.

In mammalian cells, endoplasmic reticulum (ER) passively releases Ca²⁺ under steady state, but channels involved remain elusive. Here, we report that TMEM41B, an ER-resident membrane protein critical for autophagy, lipid metabolism, and viral infection, functions as an ER Ca²⁺ release channel. Biochemically, purified recombinant TMEM41B forms a concentration-dependent Ca²⁺ channel in single-channel electrophysiology assays. Cellularly, TMEM41B deficiency causes ER Ca²⁺ overload, while overexpression of TMEM41B depletes ER Ca²⁺. Immunologically, ER Ca²⁺ overload leads to upregulation of IL-2 and IL-7 receptors in naive T cells, which in turn increases basal signaling of JAK-STAT, AKT-mTOR, and MAPK pathways. This dysregulation drives TMEM41B-deficient naive T cells into a metabolically activated yet immunologically naive state. ER Ca²⁺ overload also downregulates CD5, lowering the activation threshold of TMEM41B-deficient T cells and leading to heightened T cell responses during infections. In summary, we identify TMEM41B as a concentration-dependent ER Ca²⁺ release channel, revealing an unexpected role of ER Ca²⁺ in naive T cell quiescence and responsiveness.