Induced Treg Cells Augment the Th17-Mediated Intestinal Inflammatory Response in a CTLA4-Dependent Manner

PLOS ONE, Dec 2019

Th17 cells and Foxp3+ regulatory T cells (Tregs) are thought to promote and suppress inflammatory responses, respectively. However, whether they counteract each other or synergize in regulating immune reactions remains controversial. To determine their interactions, we describe the results of experiments employing mouse models of intestinal inflammation by transferring antigen-specific Th cells (Th1, Th2, and Th17) differentiated in vitro followed by the administration of the cognate antigen via enema. We show that cotransfer of induced Tregs (iTregs) suppressed Th1- and Th2-mediated colon inflammation. In contrast, colon inflammation induced by transfer of Th17 cells, was augmented by the cotransfer of iTregs. Furthermore, oral delivery of antigen potentiated Th17-mediated colon inflammation. Administration of a blocking antibody against cytotoxic T lymphocyte-associated antigen 4 (CTLA4) abrogated the effects of cotransfer of iTregs, while the injection of a soluble recombinant immunoglobulin (Ig) fusion protein, CTLA4-Ig substituted for the cotransfer of iTregs. These results suggest that antigen-specific activation of iTregs in a local environment stimulates the Th17-mediated inflammatory response in a CTLA4-dependent manner.

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Induced Treg Cells Augment the Th17-Mediated Intestinal Inflammatory Response in a CTLA4-Dependent Manner

March Induced Treg Cells Augment the Th17- Mediated Intestinal Inflammatory Response in a CTLA4-Dependent Manner Nobumasa Watanabe 0 1 Osamu Kaminuma 0 1 Noriko Kitamura 0 1 Takachika Hiroi 0 1 0 Allergy and Immunology Project, Tokyo Metropolitan Institute of Medical Science , Tokyo , Japan 1 Editor: Hiroshi Shiku, Mie University Graduate School of Medicine , JAPAN Th17 cells and Foxp3+ regulatory T cells (Tregs) are thought to promote and suppress inflammatory responses, respectively. However, whether they counteract each other or synergize in regulating immune reactions remains controversial. To determine their interactions, we describe the results of experiments employing mouse models of intestinal inflammation by transferring antigen-specific Th cells (Th1, Th2, and Th17) differentiated in vitro followed by the administration of the cognate antigen via enema. We show that cotransfer of induced Tregs (iTregs) suppressed Th1- and Th2-mediated colon inflammation. In contrast, colon inflammation induced by transfer of Th17 cells, was augmented by the cotransfer of iTregs. Furthermore, oral delivery of antigen potentiated Th17-mediated colon inflammation. Administration of a blocking antibody against cytotoxic T lymphocyte-associated antigen 4 (CTLA4) abrogated the effects of cotransfer of iTregs, while the injection of a soluble recombinant immunoglobulin (Ig) fusion protein, CTLA4-Ig substituted for the cotransfer of iTregs. These results suggest that antigen-specific activation of iTregs in a local environment stimulates the Th17-mediated inflammatory response in a CTLA4-dependent manner. - OPEN ACCESS Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: Support was provided by a Genomics for agricultural innovation GMC0009 project grant (TH) and Agri-Health 2 (TH) from the Ministry of Agriculture, Forestry and Fisheries of Japan. Competing Interests: The authors have declared that no competing interests exist. Introduction Accumulating evidence indicates that CD4+ helper T cells play a central role in eliciting normal immune responses and in inducing inappropriate reactions leading to allergy and autoimmune diseases [ 1 ]. For example, CD4+ regulatory T cells (Tregs) that express the transcription factor FoxP3 represent a distinct cell population with immunnosuppressive function [ 1–3 ]. In contrast, effector CD4+ helper T cells are classified mainly into Th1, Th2, and Th17 subsets that induce physiological immune responses depending on the infectious pathogens. Unless attenuated after elimination of pathogens, or maintained tolerance to self or innocuous antigens, activation of these effector subsets initiates allergic or inflammatory disorders. The idea that an aberrant Th2-type immune response induces allergy and is regulated by FoxP3+ Tregs is consistent with the results of studies on humans and numerous mouse models [ 4–6 ]. In contrast, the pathogenic role of Th17 cells on the development of autoimmune and inflammatory disorders remains controversial although the vast majority of recent findings from genome-wide studies of humans and mouse models support the intimate involvement of this subset in promoting the diseases [ 7–9 ]. This ambiguity may be explained as follows. First, most studies employ mouse models, including spontaneous occurrence of the diseases, which are driven by combinations of various T cell subsets, resembling human disease [ 10 ], which impedes the evaluation of the contribution of Th17 cells to pathogenesis. Second, the properties of Th17 cells are diverse and highly plastic in terms of immunological functions, including immune suppression under certain conditions [ 11–13 ]. Therefore, whether Th17-type immunity is susceptible to immunological tolerance or suppression mediated by FoxP3+ Tregs remains largely unknown. Moreover, evidence indicates that Tregs support the development of Th17 cells or promote Th17-mediated immunological responses [ 14–18 ] by secreting TGF-beta [ 19 ] or by consumption of IL-2 [ 17, 18 ]. Irrespective of the outcomes of interactions between Th17 cells and Tregs, the role of antigen specificity must be considered. Therefore, to delineate the outcomes caused by one-to-one interactions between iTregs and each effector T cells from otherwise complex immunological responses, we employed a model in which antigen-specific CD4+ T cells are adoptively transferred in combination followed by antigen delivery. We show here that the differential effects of iTregs depending on the effector subsets, and that CTLA4 is critically involved in both processes, inhibition of Th1/Th2-mediated colon inflammation and stimulation of Th17-mediated colon inflammation. Results and Discussion Antigen-specific effector cells induce colon thickening CD4+ T cells were obtained from spleen and mesenteric lymph nodes of DO11.10 transgenic mice with a Rag2-deficient background (DO11.10+:Rag2 K (...truncated)


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Nobumasa Watanabe, Osamu Kaminuma, Noriko Kitamura, Takachika Hiroi. Induced Treg Cells Augment the Th17-Mediated Intestinal Inflammatory Response in a CTLA4-Dependent Manner, PLOS ONE, 2016, 3, DOI: 10.1371/journal.pone.0150244