Signals through GITR program CD4+ T cells to enhance interleukin-9 production, which mediates antitumor CTL responses (LYM3P.735)

Abstract

Abstract IL-9-producing T helper cells called Th9 have been a recently identified Th subset diverted from Th2 cells and proved to mediate allergic inflammation and tumor immunity. However, the regulation of Th9 development and functions in diseases remain to be elucidated. Here, we showed that GITR costimulation could induce tumor regression by promoting IL-9 expression on CD4+ T cells. GITR signaling intrinsically enhanced IL-9 expression regardless of cytokine milieu from CD4+ T cells, and furthermore in the presence of TGF-β, could induce IL-9-producing T cells independently of IL-4 in vitro. GITR activation increased the expression of Th9-related transcription factors, Irf4, Gata3 and Batf. In addtion, GITR activated the NF-κB signaling pathway and blockade of NF-κB signaling diminished the increase of IL-9 production from CD4+ T cells by GITR. In vivo GITR ligation augmented cytotoxic T cell responses in mouse tumor models and neutralization of IL-9 led to decrease the cytotoxicity of CD8+ T cells, resultingly impeded tumor regression by anti-GITR Ab. Upregulation of CTL responses was accompanied by the amplication through increasing the maturation and cross-presentaion of infiltrating DCs, regulated by IL-9. Thus, our studies reveal the link between GITR signaling and IL-9, providing a rationale for GITR-induced antitumor immune responses.