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Glucocorticoid-induced tumor necrosis factor receptor–related protein co-stimulation facilitates tumor regression by inducing IL-9–producing helper T cells
Il-Kyu Kim; Yeonseok Chung,Chang-Yuil Kang
Nature medicine
This paper is an early paper about the role of GITR in Th9 differentiation.GITR(also known as TNFRSF18) is a co-stimulatory molecule of the TNF receptor superfamily that has emerged as a promising target for cancer immunotherapy. Although, T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models, the underlying mechanism of action remains unclear. Once activated, naïve CD4 T cells differentiated into effector T cells with distinct immune-regulatory function. Usually, CD4 T cells can be divided into four subtypes: TH1, TH2, TH17 andTregs. In recent years some new CD4 T cell subsets were discovered and became the research focus in the immunology research area. TH9 cells, a newly defined T cell subset, they played an important role in protective immunity, as well as in allergic inflammation, autoimmune diseases and importantly, in anti-tumor immunity. In this paper, the author firstly described the crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. Firstly, theydemonstrated crucial roles of CD4+ T cells and IL-4Ra signaling in mediating DTA-1–induced tumor regression. Then they examined the involvement of TH2 and TH9 cells in the tumor regression induced by DTA-1. Results showed that DTA-1 exerts antitumor activity by triggering IL-9 production from CD4+ T cells. Further study focused on how IL-9 enhanced the anti-tumor immunity. Next, they analyzed the effects of GITR signaling on the differentiation of CD4+ T cells and found that GITR co-stimulation preferentially promotes IL-9 production by mouse and human CD4+ T cells in a T cell–intrinsic manner.Mechanically, treatment with DTA-1 alters the balance between Treg and effector T cells andTRAF6–NF-kB pathway is required for GITR-induced TH9 cells.
This paper unveiled that the GITR–TRAF6–NF-κB pathway potentiates the differentiation of TH9 cells in vitroand that this may facilitate antitumor cytotoxic T cell responses by promoting the function of tumor-associated DCs.This paper reveals a novel mechanism of TH9 cell differentiation that is mediated by GITR co-stimulation and provides a fundamental basis for the clinical trials of GITR agonists.
doi:10.1038/nm.3922
02
GITR subverts Foxp3+Tregs to boost Th9 immunity through regulation of histone acetylation
Xiang Xiao1,*, Xiaomin Shi1,*, Yihui Fan1, Xiaolong Zhang1, Minhao Wu1, Peixiang Lan1, Laurie Minze1,Yang-Xin Fu2, Rafik M. Ghobrial1,3, Wentao Liu1 & Xian Chang Li1,3
NatureCommunication
This paper is about the role of GITR signaling in the regulation of CD4 T cell differentiation. Once activated, naïve CD4 T cells differentiated into effector T cells with distinct immune-regulatory function. Usually, CD4 T cells can be divided into four subtypes: TH1,TH2, TH17 and Tregs. In recent years some newCD4 T cell subsets were discovered and became the research focus in the immunology research area. TH9 cells , a newly defined T cell subset, they played an important role in protective immunity, as well as in allergic inflammation, autoimmune diseases and importantly, in anti-tumor immunity. So, it is important to understand the generation of Tregs and TH9 cells. ActivatedCD4+ T cells express multiple TNFR superfamily costimulatory molecules, including glucocorticoid-induced TNFR-related protein (GITR), but its contributions to the intricate programs of T-helper cell differentiation process are less well studied. In this paper, the authors performed the CD4 T Cells polarization in vitro with or without GITR signaling, results showed that GITR is uniquely linked to the reciprocal induction of iTregs and Th9 cells, cell types with strikingly different functions in vivo. To gain further insights, they analysed the signaling process of polarizing cytokines, transcription status of Foxp3 and IL-9 loci, as well as epigenetic changes at the Foxp3 and IL-9 loci in CD4+ naïve T cells polarized under iTreg conditions with or without GITR ligation and demonstrated the importance of histone de acetylation in GITR-mediated suppression of Foxp3 induction. Further study they confirmed that NF-KB -p50 played an important role in GITR mediated suppression of iTregs generation. They also confirmed that Foxp3 was a potent repressor of IL-9 gene expression. Then they focused on how GITR signaling induced the TH9 cells generation, results showed that GITR activates STAT6 andSTAT6 recruits histone acetyltransferase p300 to open IL-9 locus and mediateTh9 induction. At last, they confirmed their finding in vivo by using a tumor model.
This paper reports a new understanding about the role of GITR signaling iTregs andTH9 generation and suggest that therapeutic approaches targeting GITR signaling pathways or GITR triggered epigenetic mechanisms may provide additional means of therapeutic intervention in immune mediated diseases.
DOI: 10.1038/ncomms9266
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