CRAC Channels and Calcium Signaling in T Cell-Mediated Immunity. Issue 10 (October 2020)

• Record Type: Journal Article
• Authors: Vaeth, Martin; Kahlfuss, Sascha; Feske, Stefan
• Is Part Of: Trends in immunology. Volume 41:Issue 10(2020)
• Page Start: 878
• Page End: 901
• Publication Date: 2020-10
• Subjects: Calcium -- CRAC channel -- ORAI -- STIM -- Lymphocyte -- T cell; Immunology -- Periodicals; 571.96
• DOI: 10.1016/j.it.2020.06.012
• Languages: English
• ISSNs: 1471-4906

Abstract

Abstract : Calcium (Ca 2+ ) signals play fundamental roles in immune cell function. The main sources of Ca 2+ influx in mammalian lymphocytes following antigen receptor stimulation are Ca 2+ release-activated Ca 2+ (CRAC) channels. These are formed by ORAI proteins in the plasma membrane and are activated by stromal interaction molecules (STIM) located in the endoplasmic reticulum (ER). Human loss-of-function (LOF) mutations in ORAI1 and STIM1 that abolish Ca 2+ influx cause a unique disease syndrome called CRAC channelopathy that is characterized by immunodeficiency autoimmunity and non-immunological symptoms. Studies in mice lacking Stim and Orai genes have illuminated many cellular and molecular mechanisms by which these molecules control lymphocyte function. CRAC channels are required for the differentiation and function of several T lymphocyte subsets that provide immunity to infection, mediate inflammation and prevent autoimmunity. This review examines new insights into how CRAC channels control T cell-mediated immunity. Highlights: Ca 2+ influx, or store-operated Ca 2+ entry (SOCE), through Ca 2+ release-activated Ca 2+ (CRAC) channels is essential for multiple aspects of mammalian T cell function, including the acute release of cytotoxic granules by CD8 + T cells within minutes after stimulation, the production of cytokines, and transcriptional reprogramming of T cells that leads to their differentiation into various T cell subsets or alters their metabolic state. Patients with loss-of-function (LOF) mutations in ORAI1 and STIM1, and mice with genetic deletion of Orai1, Orai2, Stim1, and Stim2 genes, have elucidated the pivotal roles of CRAC channels in the functions of T lymphocytes. These comprise CD4 + T cells including type 1 and 17 T helper (Th1, Th17) cells, T follicular helper (Tfh) cells, and regulatory T cells (Tregs), as well as CD8 + T cells that mediate autoimmunity in diseases such as multiple sclerosis and colitis, provide humoral and cellular immunity to viral infection, and maintain immune homeostasis. Different T cell subsets require different levels of SOCE for their function. Th1 and Th17 cell function is inhibited by moderate suppression of Ca 2+ influx, whereas Tfh, Treg, and CD8 + T cells are relatively resistant to suppression of CRAC channel function. This difference between T cell subsets may open a therapeutic window for the suppression of proinflammatory Th1 and Th17 cells without interfering with the function of other T cell subsets that are essential for immunity to infections and for maintaining immune tolerance.