A Murine Model of X-Linked Moesin-Associated Immunodeficiency (X-MAID) Reveals Defects in T Cell Homeostasis and Migration.

Autor:	Avery L; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, United States.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Robertson TF; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, United States.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Wu CF; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, United States.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Roy NH; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, United States.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Chauvin SD; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, United States.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Perkey E; Graduate Program in Cellular and Molecular Biology and Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, United States., Vanderbeck A; Division of Hematology/Oncology, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Maillard I; Division of Hematology/Oncology, Department of Medicine and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Burkhardt JK; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, United States.; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Jan 06; Vol. 12, pp. 726406. Date of Electronic Publication: 2022 Jan 06 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.726406
Abstrakt:	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 (moesin R171W ). 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 moesin R171W 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 moesin R171W expression. In contrast, single-positive (SP) thymocytes do not appear activated and retain high expression levels of moesin R171W . 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 moesin R171W , and will provide new insights into how the actin cortex regulates lymphocyte function. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Avery, Robertson, Wu, Roy, Chauvin, Perkey, Vanderbeck, Maillard and Burkhardt.)
Databáze:	MEDLINE
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