title: Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function.
abstract: Lrrc8a is a ubiquitously expressed gene that encodes a leucine-rich repeat (LRR)-containing protein detected at higher levels on the surface of thymocytes than on other immune cells. We generated Lrrc8a(-/-) mice to investigate the role of LRRC8A in lymphocyte development and function. Lrrc8a(-/-) mice had increased prenatal and postnatal mortality, growth retardation, and multiple tissue abnormalities. Lrrc8a(-/-) mice displayed a modest block in B cell development but intact intrinsic B cell function. In contrast, both Lrrc8a(-/-) mice and Lrrc8a(-/-)→Rag2(-/-) bone marrow chimeras exhibited a severe cell-intrinsic block in early thymic development, with decreased proliferation and increased apoptosis of thymocytes, and impaired peripheral T cell function. Thymic epithelial cells expressed an LRRC8A ligand that was critical for double-negative to double-positive thymocyte differentiation and survival in vitro. LRRC8A constitutively associated with the GRB2-GAB2 complex and lymphocyte-specific protein tyrosine kinase (LCK) in thymocytes. LRRC8A ligation activated AKT via the LCK-ZAP-70-GAB2-PI3K pathway, and AKT phosphorylation was markedly reduced in the thymus of Lrrc8a(-/-) mice. These findings reveal an essential role for LRRC8A in T cell development, survival, and function.
authors.affiliation: Division of Immunology and 2 Joint Program in Transfusion Medicine, Division of Laboratory Medicine, Boston Children's Hospital; and 3 Department of Pediatrics, 4 Department of Microbiology and Immunobiology, and 5 Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Lalit
authors.initials: L
authors.lastname: Kumar
authors.forename: Janet
authors.initials: J
authors.lastname: Chou
authors.forename: Christina S K
authors.initials: CS
authors.lastname: Yee
authors.forename: Arturo
authors.initials: A
authors.lastname: Borzutzky
authors.forename: Elisabeth H
authors.initials: EH
authors.lastname: Vollmann
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Georg
authors.initials: G
authors.lastname: Hollander
authors.forename: John P
authors.initials: JP
authors.lastname: Manis
authors.forename: P Luigi
authors.initials: PL
authors.lastname: Poliani
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal; D002454:Cell Differentiation / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D005434:Flow Cytometry; D015151:Immunoblotting; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000502:physiology*; D060168:Thymocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; C000589080:LRRC8A protein, mouse; D008565:Membrane Proteins; C499308:Rag2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
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