Frontiers in Immunology (Oct 2019)
Mutation of an L-Type Calcium Channel Gene Leads to T Lymphocyte Dysfunction
- Franz Fenninger,
- Franz Fenninger,
- Franz Fenninger,
- Franz Fenninger,
- Franz Fenninger,
- Jeffrey Han,
- Shawna R. Stanwood,
- Shawna R. Stanwood,
- Shawna R. Stanwood,
- Shawna R. Stanwood,
- Shawna R. Stanwood,
- Lilian L. Nohara,
- Lilian L. Nohara,
- Lilian L. Nohara,
- Hitesh Arora,
- Hitesh Arora,
- Hitesh Arora,
- Hitesh Arora,
- Hitesh Arora,
- Kyung Bok Choi,
- Kyung Bok Choi,
- Kyung Bok Choi,
- Kyung Bok Choi,
- Lonna Munro,
- Lonna Munro,
- Lonna Munro,
- Lonna Munro,
- Cheryl G. Pfeifer,
- Cheryl G. Pfeifer,
- Cheryl G. Pfeifer,
- Cheryl G. Pfeifer,
- Iryna Shanina,
- Marc S. Horwitz,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies,
- Wilfred A. Jefferies
Affiliations
- Franz Fenninger
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Franz Fenninger
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Franz Fenninger
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
- Franz Fenninger
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Franz Fenninger
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Jeffrey Han
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Shawna R. Stanwood
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Shawna R. Stanwood
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Shawna R. Stanwood
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
- Shawna R. Stanwood
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Shawna R. Stanwood
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Lilian L. Nohara
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Lilian L. Nohara
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Lilian L. Nohara
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Hitesh Arora
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Hitesh Arora
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Hitesh Arora
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
- Hitesh Arora
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Hitesh Arora
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Kyung Bok Choi
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Kyung Bok Choi
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
- Kyung Bok Choi
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Kyung Bok Choi
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Lonna Munro
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Lonna Munro
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
- Lonna Munro
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Lonna Munro
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Cheryl G. Pfeifer
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Iryna Shanina
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Marc S. Horwitz
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
- Wilfred A. Jefferies
- Department of Zoology, University of British Columbia, Vancouver, BC, Canada
- DOI
- https://doi.org/10.3389/fimmu.2019.02473
- Journal volume & issue
-
Vol. 10
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.
Keywords
