Abstract
X-linked moesin associated immunodeficiency (X-MAID) is a primary immunodeficiency disease in which patients suffer from profound lymphopenia leading to recurrent infections. The disease is caused by a single point mutation leading to a R171W amino acid change in the protein moesin (moesinR171W). Moesin is a member of the ERM family of proteins, which reversibly link the cortical actin cytoskeleton to the plasma membrane. Here, we describe a novel mouse model with global expression of moesinR171W that recapitulates multiple facets of patient disease, including severe lymphopenia. Further analysis reveals that these mice have diminished numbers of thymocytes and bone marrow precursors. X-MAID mice also exhibit systemic inflammation that is ameliorated by elimination of mature lymphocytes through breeding to a Rag1-deficient background. The few T cells in the periphery of X-MAID mice are highly activated and have mostly lost moesinR171W expression. In contrast, single-positive (SP) thymocytes do not appear activated and retain high expression levels of moesinR171W. Analysis of ex vivo CD4 SP thymocytes reveals defects in chemotactic responses and reduced migration on integrin ligands. While chemokine signaling appears intact, CD4 SP thymocytes from X-MAID mice are unable to polarize and rearrange cytoskeletal elements. This mouse model will be a valuable tool for teasing apart the complexity of the immunodeficiency caused by moesinR171W, and will provide new insights into how the actin cortex regulates lymphocyte function.
Highlights
Protective immune responses depend on regulated actin cytoskeletal dynamics, which direct cell migration, adhesion and signaling [1,2,3,4,5]
A novel combined immunodeficiency disease termed X-linked moesin associated immunodeficiency (X-MAID) has recently been described in patients bearing a specific point mutation in the actin linker protein moesin [9,10,11,12]
The few T cells that are present in the periphery have a highly activated phenotype, and most have lost moesin expression
Summary
Protective immune responses depend on regulated actin cytoskeletal dynamics, which direct cell migration, adhesion and signaling [1,2,3,4,5]. One or more members of this highly homologous group of proteins is expressed in most cell types; T cells express high levels of moesin, moderate levels of ezrin, and little to no radixin [15] These proteins are comprised of an Nterminal 4.1-ezrin-radixin-moesin (FERM) domain, a flexible linker, and a C-terminal actin binding domain (ABD). Constitutively active mutants of ezrin or moesin prevent appropriate cytoskeletal rearrangement Lymphocytes expressing these mutants are abnormally rigid, polarize poorly, and display defective migratory responses in vitro and in vivo [22, 23, 25, 26]. Though T cells express both ezrin and moesin, deletion of ezrin in the T cell compartment has little effect on T cell trafficking [15], and the effect of deleting both ezrin and moesin is only slightly more severe than deleting moesin alone [29], indicating that moesin is the most important ERM family member in T cells
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