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

Franz Fenninger,Lilian L Nohara,Hitesh Arora,Cheryl G Pfeifer,Marc S Horwitz,Lonna Munro,Iryna Shanina,Wilfred A Jefferies,Jeffrey Han,Shawna R Stanwood,Kyung Bok Choi

doi:10.3389/fimmu.2019.02473

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 CaV channels. Here we describe a mutation in the L-type Ca2+ channel CaV1.4 leading to T lymphocyte dysfunction, including several hallmarks of immunological exhaustion. CaV1.4-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 CaV1.4-deficient mice. This is the first example where the mutation of a CaV channel leads to T lymphocyte dysfunction, including the upregulation of several inhibitory receptors, hallmarks of T cell exhaustion, and establishes the physiological importance of CaV channel signaling in maintaining a nimble immune system.

Highlights

Ca2+ is a vital signaling molecule in all cells including immune cells and controls important processes like differentiation, homeostasis, activation, proliferation, and apoptosis [1]
After verifying the disruption of the Cacna1f gene we investigated details of the T lymphocyte phenotype affected by the CaV1.4 deficiency
We initially examined the abundance of CD4 and CD8 T lymphocytes as well as B lymphocytes in these mice and found that CaV1.4 deficiency in mice led to a modest reduction of CD8 T lymphocyte frequency

Summary

Introduction

Ca2+ is a vital signaling molecule in all cells including immune cells and controls important processes like differentiation, homeostasis, activation, proliferation, and apoptosis [1]. In lymphocytes, crosslinking the antigen receptor activates a signaling cascade that eventually leads to Ca2+ release from the endoplasmic reticulum (ER) into the cytoplasm [2]. CaV1.4 Deficiency Leads to T Lymphocyte Dysfunction space is triggered. This process is called store-operated Ca2+ entry (SOCE) and the main plasma membrane channel involved in it is coined Ca2+ release-activated Ca2+ (CRAC) channel [3]. The CRAC channel consists of the pore-forming unit called ORAI1 and a Ca2+-sensing protein named STIM1 that detects low levels of Ca2+ in the ER to activate the channel. Loss-offunction mutations in ORAI1 or STIM1 genes result in the partial abrogation of SOCE and defective T cell activation [4,5,6,7]

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Results

Conclusion