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J Allergy Clin Immunol. 2017 Dec;140(6):1651-1659.e1. doi: 10.1016/j.jaci.2016.12.974. Epub 2017 Feb 10.

Leucine-rich repeat containing 8A (LRRC8A)-dependent volume-regulated anion channel activity is dispensable for T-cell development and function.

Author information

1
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
2
Department of Cardiology, Boston Children's Hospital, Boston, Mass.
3
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
4
Department of Epigenetics and Molecular Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Smithville, and the Graduate School of Biomedical Sciences at Houston, Houston, Tex.
5
Department of Cardiology, Boston Children's Hospital, Boston, Mass; Howard Hughes Medical Institute, Chevy Chase, Md.
6
Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Mass. Electronic address: raif.geha@childrens.harvard.edu.

Abstract

BACKGROUND:

Leucine-rich repeat containing 8A (LRRC8A) is an ubiquitously expressed transmembrane protein with 17 leucine-rich repeats (LRRs) at its C-terminal end and is an essential component of the volume-regulated anion channel (VRAC), which controls cellular volume. A heterozygous mutation in LRRC8A that truncates the 2 terminal LRRs was reported in a patient with agammaglobulinemia and absent B cells and was demonstrated to exert a dominant negative effect on T- and B-cell development in mice. Lrrc8a-/- mice have severely defective T-cell development and function. It is not known whether the T- and B-cell defects caused by LRRC8A deficiency are caused by loss of VRAC activity.

OBJECTIVE:

We sought to determine whether VRAC activity is required for normal T-cell development and function.

METHODS:

VRAC activity was examined by using patch-clamp analysis. Flow cytometry was used to examine T-cell development. T-cell proliferation, cytokine secretion, and antibody titers were measured by using standard techniques.

RESULTS:

We demonstrate that the spontaneous mouse mutant ébouriffé (ebo/ebo) harbors a homozygous 2-bp frameshift mutation in Lrrc8a that truncates the 15 terminal LRRs of LRRC8A. The Lrrc8aebo mutation does not affect protein expression but drastically diminishes VRAC activity in T cells. ebo/ebo mice share features with Lrrc8a-/- mice that include curly hair, infertility, reduced longevity, and kidney abnormalities. However, in contrast to Lrrc8a-/- mice, ebo/ebo mice have normal T-cell development and function and intact antibody response to T-dependent antigen.

CONCLUSION:

LRRC8A-dependent VRAC activity is dispensable for T-cell development and function.

KEYWORDS:

Leucine-rich repeat containing 8A; thymocyte development; volume-regulated anion channel

PMID:
28192143
PMCID:
PMC6170198
DOI:
10.1016/j.jaci.2016.12.974
[Indexed for MEDLINE]
Free PMC Article

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