Novel LMW inhibitors of ITPKb block autoimmune disease by promoting calcium-induced T lymphocyte death (P5165)

Abstract

Abstract Lymphocyte antigen receptor-mediated production of Ins(1,4,5)P3 induces the release of Ca2+ from intracellular stores, resulting in the opening of store-operated Ca2+ (SOC) channels. Mice deficient in inositol(1,4,5)P3-3 kinase B (ITPKb), which converts inositol(1,4,5)P3 (IP3) to inositol(1,3,4,5)P4 (IP4), exhibit a complete block in T cell positive selection. Previous studies demonstrated that IP4 is an inhibitor of SOC channels. To understand the role of ITPKb in mature peripheral lymphocytes, inducible ITPKb-/- mice were generated. Deletion of ITPKb in mature lymphocytes reveals that ITPKb is required for mature T cell function and T-dependent antibody responses. Following antigen receptor activation, the loss of ITPKb leads to enhanced Ca2+ levels and the induction of death effector gene expression resulting in apoptosis. We further demonstrate that IP4 is an inhibitor of open-state Orai1 channels. LMW ITPKb inhibitors were identified using a high-throughput compound screen. Application of ITPKb inhibitors to lymphocytes enhanced Ca2+ responses following antigen receptor stimulation, similar to ITPKb-/- cells. Treatment of mice with ITPKb inhibitors recapitulated the block in T cell development observed in ITPKb-/- mice and inhibited antigen-induced arthritis formation in rats. These data identify ITPKb and IP4 as crucial mediators of lymphocyte development and activation, and suggest that inhibition of ITPKb may provide a novel mechanism to treat autoimmune disease.