Hyperactivated PI3Kδ skews unconventional T cell differentiation 4224

Abstract Description Activated PI3K delta syndrome (APDS) is an inborn error of immunity (IEI) characterized by activating mutations in PI3Kδ, with patients showing recurrent respiratory infections, and autoimmunity, including some skin pathologies. While the role of conventional T cells has been well characterized in APDS, the role of unconventional T cells is unclear. In mice, γδ T cells, a critical unconventional T cell population residing within numerous barrier sites, utilize distinct Vγ gene segments, encoding T cell receptors that recognize non-MHC molecules, which dictate their unique functional properties and tissue homing. To address the role of activated PI3Kδ in unconventional T cell development, we investigated the generation of these cells in wild-type (WT) and Pik3cdE1020K/+ mice, a model of APDS. Adult Pik3cdE1020K/+ thymi showed dramatically altered γδ T cell development, with significantly increased numbers and frequencies of Rorγt expressing γδ17 cells, including Vγ4-expressing γδ T cells. Skin contains high numbers of γδ17 cells, with inappropriate activity of these cells driving skin diseases such as psoriasis and atopic dermatitis. Pik3cdE1020K/+ mice showed significantly elevated numbers and frequencies of γδ17 cells within the skin, including fetal-derived Vγ6-expressing γδ T cells. While the role of unconventional T cells in IEIs is underappreciated, alterations in unconventional T cells in APDS may reveal new roles of these unique lymphocytes in disease pathogenesis. Funding Sources This research was supported by the Division of Intramural Research of NIAID, NIH. Topic Categories Hematopoiesis and Immune System Development (HEM)