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

Autor: Fenninger F; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Han J; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada., Stanwood SR; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Nohara LL; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Arora H; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Choi KB; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Munro L; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Pfeifer CG; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada., Shanina I; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada., Horwitz MS; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada., Jefferies WA; Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.; Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.; Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.; The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.; Department of Zoology, University of British Columbia, Vancouver, BC, Canada.
Jazyk: angličtina
Zdroj: Frontiers in immunology [Front Immunol] 2019 Oct 29; Vol. 10, pp. 2473. Date of Electronic Publication: 2019 Oct 29 (Print Publication: 2019).
DOI: 10.3389/fimmu.2019.02473
Abstrakt: Calcium (Ca 2+ ) 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 Ca 2+ channel Ca V 1.4 leading to T lymphocyte dysfunction, including several hallmarks of immunological exhaustion. Ca V 1.4-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 Ca 2+ flux compared to wild-type controls. Finally, modifying environmental conditions by herpes virus infection exacerbated the dysfunctional immune phenotype of the Ca V 1.4-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.
(Copyright © 2019 Fenninger, Han, Stanwood, Nohara, Arora, Choi, Munro, Pfeifer, Shanina, Horwitz and Jefferies.)
Databáze: MEDLINE
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