PI3Kδ drives the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation

The Class IA phosphoinositide 3-kinase delta (PI3K delta) has been implicated in multiple signaling pathways involved in leukocyte activation and hence is an attractive target in many human autoimmune diseases, including multiple sclerosis (MS). Here, using mice expressing a catalytically inactive form of the PI3K delta subunit p110 delta, we show that signaling through P13K delta is required for full and sustained pathology of experimental autoimmune encephalomyelitis (EAE), a Th17-driven model of MS. In p110 delta-inactivated mice, T cell activation and function during EAE was markedly reduced and fewer T cells were observed in the central nervous system (CNS). The decrease in T cell activation is unlikely to be due to defects in dendritic cell (DC) function, as p110 delta-inactivated DCs migrate and present antigen normally. However, significant increases in the proportion of T cells undergoing apoptosis at early stages of EAE were evident in the absence of PI3K delta activity. Furthermore, a profound defect in Th17 cellular responses during EAE was apparent in the absence of PI3K delta activity while Th1 responses were less affected. A highly selective PI3K delta inhibitor, IC87114, also had greater inhibitory effects on Th17 cell generation in vitro than it did on Th1 cell generation. Thus, PI3K delta plays an important role in Th17 responses in EAE, suggesting that small molecule inhibitors of PI3K delta may be useful therapeutics for treatment of MS and other autoimmune diseases. (C) 2011 Elsevier Ltd. All rights reserved.