Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function
In: Journal of Experimental Medicine, Jg. 211 (2014-04-21), S. 929-942
Online
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Zugriff:
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.
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Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function
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Autor/in / Beteiligte Person: | Geha, Raif S. ; Chou, Janet ; Park, Shin-Young ; Vollmann, Elisabeth H. ; Christina S.K. Yee ; P. Luigi Poliani ; Ulrich H. von Andrian ; Borzutzky, Arturo ; Kumar, Lalit ; Holländer, Georg A. ; Manis, John P. |
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Zeitschrift: | Journal of Experimental Medicine, Jg. 211 (2014-04-21), S. 929-942 |
Veröffentlichung: | Rockefeller University Press, 2014 |
Medientyp: | unknown |
ISSN: | 1540-9538 (print) ; 0022-1007 (print) |
DOI: | 10.1084/jem.20131379 |
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