The CaV1.4 Calcium Channel Is a Critical Regulator of T Cell Receptor Signaling and Naive T Cell Homeostasis

SummaryThe transport of calcium ions (Ca2+) to the cytosol is essential for immunoreceptor signaling, regulating lymphocyte differentiation, activation, and effector function. Increases in cytosolic-free Ca2+ concentrations are thought to be mediated through two interconnected and complementary mechanisms: the release of endoplasmic reticulum Ca2+ “stores” and “store-operated” Ca2+ entry via plasma membrane channels. However, the identity of molecular components conducting Ca2+ currents within developing and mature T cells is unclear. Here, we have demonstrated that the L-type “voltage-dependent” Ca2+ channel CaV1.4 plays a cell-intrinsic role in the function, development, and survival of naive T cells. Plasma membrane CaV1.4 was found to be essential for modulation of intracellular Ca2+ stores and T cell receptor (TCR)-induced rises in cytosolic-free Ca2+, impacting activation of Ras-extracellular signal-regulated kinase (ERK) and nuclear factor of activated T cells (NFAT) pathways. Collectively, these studies revealed that CaV1.4 functions in controlling naive T cell homeostasis and antigen-driven T cell immune responses.

► CaV1.4 is required for store-operated calcium entry by naive CD4+ and CD8+ T cells ► CaV1.4 regulates TCR-induced Ras-ERK and NFAT signaling ► CaV1.4 modulates the survival of naive CD4+ and CD8+ T cells ► Cav1.4 is critical for pathogen-specific CD4+ and CD8+ T cell responses