039 IL-7 regulates the PD-1 signaling pathway via degradation by E3 ubiquitin ligase F-Box Protein 38

Abstract

Alopecia areata (AA) is a T cell-mediated autoimmune disease attacking the hair follicle (HF). The IL-7 signaling pathway plays an important role in T cell survival and it has been therapeutically targeted in several T cell-dependent autoimmune disease models. Here, we showed that C3H/HeJ mice with AA exhibited hair regrowth after anti-IL7Ra treatment. Mechanistically, we observed that IL-7Ra blockade significantly reduced the number of alopecic effector CD8+ T cells. We also found that C3H/HeJ mice treated with anti-IL-7Rα showed a significant increase in the frequency of PD-1+CD44+ T cells within SDLNs compared to controls. Our previous results indicated that IL-7 may antagonize the function of PD-1 by downregulating the expression of PD-1 in T cells, however, the mechanism of this downregulation remains unclear. Recently, the F-box protein FBXO38, a member of the SKP1–CUL1–F-box protein family of E3 ubiquitin ligases, has shown to interact with PD-1 and decrease PD-1 cell-surface expression via degradation. Based on this findings, we postulated that IL-7 might decrease PD-1 expression through upregulation of FBXO38. We found that IL-7 significantly increased the transcription levels of FBXO38 and concurrently decreased the expression of PD-1 on the surface of T cells in vitro. We further observed that FBXO38 knockdown using siRNA increased the PD-1 expression on the surface of T cells compared to control, and moreover, this effect could not be rescued by IL-7 treatment. Our results indicate FBXO38 as a critical mediator of PD-1 degradation and suggests that targeting IL-7-mediated regulation of FBXO38 expression may represent a potential strategy to enhance PD-1 signaling in T cell-mediated autoimmune diseases including AA.