Signals through GITR program CD4+ T cells to induce interleukin-9 (163.9)

Abstract

Abstract Glucocorticoid-induced TNF receptor family-related protein (GITR) is expressed on various immune cells and well known as one of the co-stimulatory molecules to promote T helper (Th) type 2 responses. In this study, we show that an agonistic anti-GITR mAb (clone DTA-1) induced IL-9 production on the committing Th2 and regulatory T (Treg) cells, as well as enhanced IL-9 production from naive CD4+ T cells under Th9 skewing condition. Whereas, DTA-1 did not induce IFN-γ or IL-17A, lineage-specific cytokines of Th1 or Th17, respectively and was resistant to produce IL-9 from naive CD4 T cells under Th1 or Th17 polarizing conditions. Furthermore, GITR stimulation promoted reprogramming of regulatory T cells to produce IL-9+Foxp3+ Treg and effector Th9 cells. We found transcription factor Interferon-regulatory factor4 (IRF4) was up-regulated by GITR ligation at the early stage of Th9 differentiation and contributed to enhance IL-9 production. Also, when GITR signaling was activated, p65, activated by NFκB signaling pathways, directly interacted with Il9 locus including promoter region at the later stage of Th9 differentiation. Consistent with in vitro study, in vivo administration of DTA-1 enhanced IL-9 at the transcript level and the roles of IL-9 induced by GITR ligation in vivo are remained to be investigated for further studies.