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bioRxiv · 10.1101/2024.11.21.624633

Loss of PI3Kδ activity drives autoimmune colitis by impairing extrathymic Treg differentiation

Lim, E. L.·Qian, Y.·Sugihara, F.·Tanaka, A.·Sakaguchi, S.
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Abstract

Peripherally-derived regulatory T cells (pTregs) have a prominent role in maintaining intestinal immune homeostasis. In cases of phosphoinositide-3-kinase {delta} (PI3K{delta}) inactivation, such as in patients receiving PI3K{delta} inhibitor idelalisib as a cancer treatment, breakdown of intestinal immune tolerance occurs frequently in the form of diarrhoea and colon inflammation. In a mouse model of systemic PI3K{delta} inactivation, both enhancement of anti-tumor 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 PI3K{delta} function is not yet understood. We report here that mice lacking PI3K{delta} activity do not suffer a general defect in Treg immunosuppression, but specifically fail to develop Helios- pTregs in the colon. We demonstrate reduced extrathymic Treg induction, in vitro and in vivo, from naive CD4+ T cells with inactive PI3K{delta}, along with dysregulation of a tissue-resident phenotype. These results suggest a non-redundant role for PI3K{delta}-dependent pTreg differentiation in maintaining tolerance to commensal microbial antigens in the gut.

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Lim, E. L., Qian, Y., Sugihara, F., Tanaka, A., Sakaguchi, S.. 2024-11-21. Loss of PI3Kδ activity drives autoimmune colitis by impairing extrathymic Treg differentiation. https://doi.org/10.1101/2024.11.21.624633

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