Human tumor‐infiltrating Th17 cells have the capacity to differentiate into IFN‐γ⁺ and FOXP3⁺ T cells with potent suppressive function

Abstract

Accumulating evidence suggests that Th17 cells and Tregs may exhibit development plasticity and that CD41 Tregs can differentiate into IL-17-producing T cells; however, whether Th17 cells can reciprocally convert into Tregs has not been described. In this study, we generated Th17 clones from tumor-infiltrating T lymphocytes (TILs). We showed that Th17 clones generated from TILs can differentiate into IFN-c-producing and FOXP3 1 cells after in vitro stimulation with OKT3 and allogeneic peripheral blood mononuclear cells. We further demonstrated that T-cell receptor (TCR) engagement was responsible for this conversion, and that this differentiation was due to the epigenetic modification and reprogramming of gene expression profiles, including lineage-specific transcriptional factor and cytokine genes. In addition to expressing IFN-c and FOXP3, we showed that these differentiated Th17 clones mediated potent suppressive function after repetitive stimulation with OKT3, suggesting that these Th17 clones had differentiated into functional Tregs. We further demonstrated that the Th17-derived Tregs, unlike naturally occurring CD4 1 CD25 1 Tregs, did not reconvert back into Th17 cells even under Th17-biasing cytokine conditions. These results provide the critical evidence that human tumor-infiltrating Th17 cells can differentiate into Tregs and indicate a substantial developmental plasticity of Th17 cells.Keywords: IL-17 . Treg . T-cell development . Th17Supporting Information available online IntroductionRecent discovery of two novel T-cell subsets, Th17 and Tregs, has resulted in an explosion of immunological research that has markedly enhanced our understanding of human T-cell-mediated immunity under both physiological and pathological conditions [1,2]. It is now widely accepted that Tregs have a broad immunosuppressive capacity and play a central role in controlling immune tolerance and homeostasis of the immune system [3,4], whereas Th17 cells are important contributors to the pathogenesis of a wide array of inflammatory and autoimmune diseases [5]. 936that instruct a specific differentiation program [6][7][8]. It is now recognized that cytokines IL-12 and IFN-g are required for the polarization of Th1 cells, whereas signal transducer and activator of transcription 1 and 4 (Stat1 and Stat4) and T box transcription factor (T-bet) are critical for their regulation [6,7]. Th2-cell differentiation requires the cytokine IL-4 and the transcriptional factors GATA3 and Stat6 [6,7]. Th17-cell differentiation is dependent on the transcription factors retinoid-related orphan receptor (RORgt), Stat3 and interferon regulatory factor 4 (IRF-4) [9,10]. TGF-b and IL-6 or TGF-b and IL-21 are critical cytokines for the initiation of mouse Th17-cell differentiation [11][12][13]. Furthermore, IL-23 is critical for the in vivo function of pathogenic effectors of Th17-cells [14,15]. The differentiation and development of Tregs require TGF-b and the forkhead transcription factor, FOXP3 [16].Although different types of T-cell lineages have...

Human regulatory T cells induce T-lymphocyte senescence

“…Recent studies have shown that human FoxP3 contains several highly conserved demethylation regions that are exclusive for Treg cells. 34,35 We also observed that the Treg-specific demethylated region within the FoxP3 locus of CD4 ϩ CD25 hi Foxp3 ϩ T cells was almost completely demethylated compared with that of CD4 ϩ CD25 Ϫ T cells ( Figure 1B). We then investigated the suppressive capacity of CD4 ϩ CD25 hi FoxP3 ϩ Treg cells using functional proliferation assays.…”

A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells

“…5,[7][8][9][10][11]41 In contrast to unpolarized CD4 ϩ T cells or Th1 cells, our present findings suggest that with repeated activation, Th17 cells may gain regulatory function. In support of this possibility, after repetitive stimulation, Th17 cell clones acquire an increasingly demethylated TSDR and regulatory capacity 42 and there is evidence for suppressive IL-17 ϩ FOXP3 ϩ T cells in the blood of both healthy subjects 16,17 and colitic patients. 15 The origin of IL-17 ϩ FOXP3 ϩ cells was assumed to be the result of FOXP3 ϩ Tregs becoming unstable and acquiring IL-17 production, but our data suggest that the opposite may also be happening: Th17 cells may acquire FOXP3.…”

Heme Oxygenase-1 Exerts a Protective Role in Ovalbumin-induced Neutrophilic Airway Inflammation by Inhibiting Th17 Cell-mediated Immune Response

“…The Th17/Treg balance is considered to be critical for host immunity and the preservation of tolerance (45,46). In addition, it has been proved that Th17 cells and Tregs can be interconverted and are reciprocally regulated during differentiation dependent on the cytokine milieu (47,48). Tregs are responsible for maintaining immune homeostasis.…”