Multifaceted control of T cell differentiation by STIM1

In T cells, stromal interaction molecule (STIM) and Orai are dispensable for conventional T cell development, but critical for activation and differentiation. This review focuses on novel STIM-dependent mechanisms for control of Ca²⁺ signals during T cell activation and its impact on mitochondrial function and transcriptional activation for control of T cell differentiation and function. We highlight areas that require further work including the roles of plasma membrane Ca²⁺ ATPase (PMCA) and partner of STIM1 (POST) in controlling Orai function. A major knowledge gap also exists regarding the independence of T cell development from STIM and Orai, despite compelling evidence that it requires Ca²⁺ signals. Resolving these and other outstanding questions ensures that the field will remain active for many years to come.