Loss of PI3Kδ Activity Drives Autoimmune Colitis by Impairing Extrathymic Treg Differentiation.

Abstract

Peripherally derived regulatory T cells (pTregs) have a prominent role in maintaining intestinal immune homeostasis. In cases of phosphoinositide-3-kinase δ (PI3Kδ) inactivation, such as in patients receiving PI3Kδ inhibitor idelalisib as a cancer treatment, breakdown of intestinal immune tolerance occurs frequently in the form of diarrhea and colon inflammation. In a mouse model of systemic PI3Kδ inactivation, both enhancement of antitumor immunity and colitis have been described as a result of Treg impairment. However, in view of the critical role for Tregs in the prevention of systemic autoimmunity, the basis for such tissue-restricted breach of immune tolerance upon loss of PI3Kδ function is not yet understood. We report here that mice lacking PI3Kδ activity do not suffer a general defect in Treg immunosuppression, but specifically fail to develop HeliospTregs in the colon. We demonstrate reduced extrathymic Treg induction, in vitro and in vivo, from naïve CD4T cells with inactive PI3Kδ, along with dysregulation of a tissue-resident phenotype. These results suggest a nonredundant role for PI3Kδ-dependent pTreg differentiation in maintaining tolerance to commensal microbial antigens in the gut.