Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10

Abstract

CD4 + CD25 + Forkhead box P3 (Foxp3) + regulatory T cells (Tregs) control immune responses to self and foreign antigens in secondary lymphoid organs and at tissue sites of inflammation. Tregs can modify the function of many immune cells and have been proposed to block early proliferation, differentiation, and effector function. Acute ablation of Tregs has revealed rapid cytokine production immediately after Treg removal, suggesting that Tregs may regulate effector function acutely rather than regulating the programming for immune function. We developed in vitro and in vivo models that enabled the direct test of Treg regulation of T-helper cell type 1 (Th1) differentiation. CD28 signaling is known to abrogate Treg suppression of IL-2 secretion and proliferation, but our studies show that Treg suppression of IFN-γ during Th1 priming proceeds despite enhanced CD28 signaling. Importantly, during Th1 differentiation, Tregs inhibited early IFN-γ transcription without disrupting expression of Th1-specific T-box transcription factor (Tbet) and Th1 programming. Acute shutoff of effector cytokine production by Tregs was selective for IFN-γ but not TNF-α and was independent of TGF-β and Epstein-Barr virus-induced gene 3. In vivo, Tregs potently controlled CD4 IFN-γ and CD4 effector cell expansion in the lymph node (four-to fivefold reduction) but not Th1 programming, independent of IL-10. Tregs additionally reduced CD4 IFN-γ in the inflamed dermis (twofold reduction) dependent on their production of IL-10. We propose a model for Treg inhibition of effector function based on acute cytokine regulation. Interestingly, Tregs used different regulatory mechanisms to regulate IFN-γ (IL-10-dependent or -independent) subject to the target T-cell stage of activation and its tissue location.

Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes

“…For instance, these Treg-associated mediators are known to diminish the presence of inflammatory cytokines such as IFN-γ and IL-17 (32,33). Notably, Th type 1 (Th1) and Th17 cells, which are associated with high levels of IFN-γ and IL-17 expression, have been previously implicated to exacerbate periodontal disease symptoms (31)(32)(33)(34)(35). Consistent with the idea that recruited Tregs may regulate this process, our data (Figs.…”

“…It is well known that these regulatory cytokines are secreted by Tregs, and are a mode by which Tregs exert a protective effect (28). For instance, these Treg-associated mediators are known to diminish the presence of inflammatory cytokines such as IFN-γ and IL-17 (32,33). Notably, Th type 1 (Th1) and Th17 cells, which are associated with high levels of IFN-γ and IL-17 expression, have been previously implicated to exacerbate periodontal disease symptoms (31)(32)(33)(34)(35).…”

Engagement of Toll-like receptor 2 enhances interleukin (IL)-17+ autoreactive T cell responses via p38 mitogen-activated protein kinase signalling in dendritic cells

“…This is in line with previous studies by Lal et al and Prinz et al [35,36]. However, the relationship between reduced Treg cells and enhanced Th17 cell responses is not clear, given that Treg cells are not so effective in the control of Th17 responses as in the suppression of Th1 responses [37,38]. Consistent with our current report, Fang et al [39] reported that the single TLR-1/2 agonist Pam3CSK4 exacerbated EAU with a suboptimal immunization protocol.…”

Pathological Role of Regulatory T Cells in the Initiation and Maintenance of Eczema Herpeticum Lesions

“…Thus, an important implication of our results is that such impaired IFN-g production would be restored to the normal level by a timely decrease in Treg frequency occurring at the late stage of EH, which is the key to successful resolution of an infection. Our Treg-depletion experiments showed that IFN-g responses were more sensitive to the action of Tregs than were TNF-a responses, which are in accordance with the recent data in mice showing that acute shutoff effector cytokine production by Tregs was selective for IFN-g but not TNF-a (28). If so, therapeutic inactivation of Tregs may provide a greater benefit for protective immunity to HSV in a setting of genetically impaired IFN-g responses.…”