Activated PI3Kδ specifically perturbs mouse Treg homeostasis and function leading to immune dysregulation

Abstract

Foxp3+ regulatory T cells (Treg) are required for maintaining immune tolerance and preventing systemic autoimmunity. PI3K{delta} is required for normal Treg development and function. However, the impacts of dysregulated PI3K{delta} signaling on Treg function remain incompletely understood. Here, we used a conditional mouse model of activated PI3K{delta} syndrome (APDS) to investigate the role of altered PI3K{delta} signaling specifically within the Treg compartment. Aged mice expressing a PIK3CD gain-of-function mutation (aPIK3CD) specifically within the Treg compartment exhibited weight loss and evidence for chronic inflammation as demonstrated by increased memory/effector CD4+ and CD8+ T cells with enhanced IFN-{gamma} secretion, spontaneous germinal center responses and production of broad-spectrum autoantibodies. Intriguingly, aPIK3CD facilitated Treg precursor development within the thymus and an increase in peripheral Treg numbers. Peripheral Treg, however, exhibited an altered phenotype including increased PD1 expression and reduced competitive fitness. Consistent with these findings, Treg specific-aPIK3CD mice mounted an elevated humoral response following immunization with a T-cell dependent antigen, that correlated with a decrease in follicular Treg. Taken together, these findings demonstrate that an optimal threshold of PI3K{delta} activity is critical for Treg homeostasis and function, suggesting that PI3K{delta} signaling in Treg might be therapeutically targeted to either augment or inhibit immune responses.