Mutation of an L-Type Calcium Channel Gene Leads to T Lymphocyte Dysfunction

Abstract

Calcium (Ca²⁺) is a vital secondary messenger in T lymphocytes regulating a vast array of important events including maturation, homeostasis, activation, and apoptosis and can enter the cell through CRAC, TRP, and Ca_V channels. Here we describe a mutation in the L-type Ca²⁺ channel Ca_V1.4 leading to T lymphocyte dysfunction, including several hallmarks of immunological exhaustion. Ca_V1.4-deficient mice exhibited an expansion of central and effector memory T lymphocytes, and an upregulation of inhibitory receptors on several T cell subsets. Moreover, the sustained elevated levels of activation markers on B lymphocytes suggest that they are in a chronic state of activation. Functionally, T lymphocytes exhibited a reduced store-operated Ca²⁺ flux compared to wild-type controls. Finally, modifying environmental conditions by herpes virus infection exacerbated the dysfunctional immune phenotype of the Ca_V1.4-deficient mice. This is the first example where the mutation of a Ca_V channel leads to T lymphocyte dysfunction, including the upregulation of several inhibitory receptors, hallmarks of T cell exhaustion, and establishes the physiological importance of Ca_V channel signaling in maintaining a nimble immune system.

Keywords: CaV1.4; Cacna1f; L-type calcium channel; T cell exhaustion; T cell memory; chronic B cell activation; chronic infections; murine gammaherpesvirus 68.