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

SUMMARY Naive T cells are metabolically quiescent. Here, we report an unexpected role of endoplasmic reticulum (ER) Ca 2+ in preserving T cell metabolic quiescence. TMEM41B, an ER-resident membrane protein previously known for its crucial roles in autophagy, lipid scrabbling and viral infections, is identified as a novel type of concentration-dependent ER Ca 2+ release channel. Ablation of TMEM41B induces ER Ca 2+ overload, triggering the upregulation of IL-2 and IL-7 receptors in naive T cells. Consequently, this leads to increased basal signaling of the JAK-STAT, AKT-mTOR, and MAPK pathways, propelling TMEM41B-deficient naive T cells into a metabolically activated yet immunologically naive state. ER Ca 2+ overload also downregulates CD5, a suppressor of TCR signaling, thereby reducing the activation threshold of TMEM41B-deficient T cells, resulting in attenuated tolerance and heightened T cell responses during infections. In summary, TMEM41B-mediated ER Ca 2+ release is a pivotal determinant governing metabolic quiescence and responsiveness of naive T cells.