Abstract
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.
Highlights
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]
We show here that the differential effects of induced Tregs (iTregs) depending on the effector subsets, and that cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is critically involved in both processes, inhibition of Th1/Th2-mediated colon inflammation and stimulation of Th17-mediated colon inflammation
Cells were differentiated in vitro in a mutually exclusive manner to an interferon (IFN)-gamma-producing Th1 subset, an interleukin (IL)-4-producing Th2 subset, and an IL-17A-producing Th17 subset under each polarizing condition described in Materials and Methods (S1A Fig) [20]
Summary
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]. ITregs Enhance the Th17-Immune Response via CTLA4 the pathogenic role of Th17 cells on the development of autoimmune and inflammatory disorders remains controversial 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 [7,8,9]. This ambiguity may be explained as follows. 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
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