Leucine-rich repeat containing 8a (LRRC8A) is a novel T cell co-stimulatory receptor for T cell activation (IRC2P.453)

Abstract

Abstract LRCC8A is a ubiquitously expressed cell surface receptor necessary for lymphocyte development. The role of LRRC8A in peripheral T cell function is unknown. We now demonstrate that LRRC8A ligation enhances TCR-driven T cell proliferation and cytokine secretion. LRRC8A co-capped with the TCR/CD3 complex after anti-CD3 stimulation, and its ligation led to the phosphorylation of AKT through a Src kinase-Zap-70-PI3K pathway. A GST-LRRC8A fusion protein containing the extracellular leucine-rich region of LRRC8A bound to fibroblasts and keratinocytes, but not dendritic cells or B cells, indicating that non-professional APCs express a ligand for LRRC8A. The LRRC8A receptor-ligand interaction was essential for T cell proliferation to antigen presented by non-professional APCs, and for tissue inflammation induced by contact hypersensitivity to hapten. LRRC8A functions as a co-stimulatory receptor for T cell activation by non-professional APCs. Blocking LRRC8A signaling may be useful in the treatment of T cell-driven inflammatory diseases.