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. © 2014 Kumar et al.