Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function

Kumar, L.; Chou, J.; Yee, CSK; Borzutzky, A; Vollmann, EH; von Andrian, UH; Park, SY; Hollander, G; Manis, JP; Poliani, PL; Geha, RS

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.

Más información

Título según WOS: Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function
Título de la Revista: JOURNAL OF EXPERIMENTAL MEDICINE
Volumen: 211
Número: 5
Editorial: ROCKEFELLER UNIV PRESS
Fecha de publicación: 2014
Página de inicio: 929
Página final: 942
Idioma: English
DOI:

10.1084/jem.20131379

Notas: ISI