The development of IL‐17/IFN‐γ‐double producing CTLs from Tc17 cells is driven by epigenetic suppression of Socs3 gene promoter

Abstract

The plasticity of T lymphocytes induced by epigenetic modifications of gene promoters may play a pivotal role in controlling their effector functions, which are sometimes causally associated with immune disorders. IL -17-producing T cells, which induce type 17 immune responses, are newly identified pathogenic effector cells. The type 1 signature cytokine IFN-γ strongly inhibits their differentiation, indicating a mutually exclusive relationship between type 17-and type 1-immune responses. However, many reports indicate the presence of a unique IL-17/IFN-γ-double producing T-cell subset in various inflammatory settings, although the mechanisms responsible for their development and their precise functions remain unclear. Here, we demonstrate that IL-12 permits the conversion of mouse IL-17-producing CD8 + T (Tc17) cells to IL-17/IFN-γ-double producing CD8 + T (Tc17/IFN-γ) cells, and that this conversion is due to repressive epigenetic modifications of Socs3 gene promoters. Moreover, we show that SOCS3 strongly regulates the capability of Tc17 cells to produce IL-17, in addition to regulating the expression of the type 17-master regulator RORγt. These findings elucidate the mechanisms underlying the conversion of Tc17 cells into Tc17/IFN-γ cells. As these cells are known to have potent antitumor activities, manipulation of these conversion mechanisms for therapeutic tumor immunity may be possible. [3][4][5][6]. In particular, studies on Th17 cells enabled us to explain the precise mechanisms involved in several immune diseases, which could not be simply explained by disruption of the Th1/Th2 balance [7]. IL-17-producing CD8 + T (Tc17) cells are known to be * These authors contributed equally to this work. Keywords: Epigeneticswww.eji-journal.eu 2330 Takayuki Satoh et al. Eur. J. Immunol. 2012. 42: 2329-2342 induced under similar circumstances to Th17 cells, where IL-6 and TGF-β are crucial factors for induction and maintenance of the expression of retinoic acid-related orphan receptor γt (RORγt), the master regulator for type 17 immunity [8]. Furthermore, the presence of IFN-γ and IL-4 in the early stages negatively regulates the development of type 17 immune responses [5,6]. These reports clearly show that commitment toward a type 1, type 2, or type 17 immunity is an irreversible step, which inhibits commitment to another functional type. Although Th17/Tc17 cells are apparently distinct from the Th1/IFN-γ-producing CD8 + T (Tc1) cell lineage, recent reports have revealed that Th17/Tc17 are highly plastic and can convert to Th1/Tc1-like cells regulated by IL-12 signaling [9][10][11]. Exposure of Th17 cells to IL-12 results in STAT4/T-bet-dependent shutdown of IL-17 expression by rapid chromatin remodeling of the Il17a gene locus, while permitting IFN-γ transcription by histone modulation in the Ifng promoter region [12]. These strictly regulated mechanisms allow T cells to exhibit either type 17 or type 1 responses, and seem to be critical machinery for blocking exaggerated immune responses. This suggests a high...

Tc17 cells are a proinflammatory, plastic lineage of pathogenic CD8+ T cells that induce GVHD without antileukemic effects

“…Notably, coexpression of both IL-17A and IFNg was observed early posttransplant, which appears to be a general feature of Tc17 cells. 15,32,34 This dual expression has been attributed to epigenetic suppression of the regulatory protein SOCS3, 32 whose absence in donor T cells we have shown to also result in polyfunctional T-cell responses and exacerbated GVHD. 44 In this study, we found that Socs3 gene expression was downregulated in CD8 Table 3).…”

“…We have previously shown that in a murine model of allo-SCT, G-CSF mobilization promotes donor Th17/Tc17 differentiation and that IL-17A-deficient allografts protect recipients from CD8 1 T cellmediated sclerodermatous GVHD. 15 Recent studies in other disease 12,32,34,[39][40][41] ; however, plasticity studies of Tc17 have been limited to the use of in vitro polarized CD8 1 T cells. To circumvent this limitation, we used a murine IL-17A "fate-mapping" reporter model to characterize an inflammatory Tc17 lineage that develops during GVHD, and to our knowledge, we are the first to do so.…”

Heterogeneity in the Differentiation and Function of CD8+ T Cells

“…The cytokine IL-12 has been shown to promote the switch of Tc17 toward Tc1 via epigenetic suppression of Socs3, which on the one hand promotes Tc17 generation (Satoh et al 2012;Yu et al 2013) and on the other dampens Tc1 effector development (Cui et al 2011). Interestingly, in allergic airway disease IFN-c-deficient CD8…”

Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT

“…[1][2][3][4][5][6] Plasticity has been widely reported in CD4 IL-17A 1 (Tc17) T cells in a range of infectious and autoimmune settings. [6][7][8][9][10][11][12] We have recently described Tc17 cytokine plasticity in murine allo-SCT recipients, 1 which is characteristic of a hyper-proinflammatory T-cell subset that contributes to GVHD but fails to mediate graft-versus-leukemia effects. 1,3 Th17 cells have been reported to transdifferentiate toward highly functional distinct phenotypes, including the acquisition of regulatory and follicular B-cell helper function (Tfh).…”