Kumar, LalitChou, JanetYee, ChristinaBorzutzky, ArturoVollmann, Elisabeth H.von Andrian-Werburg, UlrichPark, Shin-YoungHollander, GeorgManis, JohnPoliani, P. LuigiGeha, Raif2014-12-022014Kumar, L., J. Chou, C. S. Yee, A. Borzutzky, E. H. Vollmann, U. H. von Andrian, S. Park, et al. 2014. “Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function.” The Journal of Experimental Medicine 211 (5): 929-942. doi:10.1084/jem.20131379. http://dx.doi.org/10.1084/jem.20131379.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:13454721Lrrc8a 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.en-USJournal Article2014-12-0210.1084/jem.20131379