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

    loading  Checking for direct PDF access through Ovid

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 inLRRC8Athat 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 mutantébouriffé (ebo/ebo)harbors a homozygous 2-bp frameshift mutation inLrrc8athat truncates the 15 terminal LRRs of LRRC8A. TheLrrc8aebomutation does not affect protein expression but drastically diminishes VRAC activity in T cells.ebo/ebomice share features withLrrc8a−/−mice that include curly hair, infertility, reduced longevity, and kidney abnormalities. However, in contrast toLrrc8a−/−mice,ebo/ebomice 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.

Related Topics

    loading  Loading Related Articles