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Characterization of regulatory T cells induced by toxic shock syndrome toxin-1 and their potential application in acute graft-versus-host disease Li, Haowei

Abstract

Repeated administration of a bacterial superantigen, toxic shock syndrome toxin-1 (TSST-1), has been shown to induce CD4+ regulatory T cells in mice. However, it is not clear if the characteristics of TSST-1-induced Tregs differ from those of Tregs induced by other bacterial superantigens, such as staphylococcal enterotoxin A (SEA). The mechanisms of T TSST-1-induced Tregs are also not well characterized. Because in experimental settings Tregs can be used to effectively treat multiple diseases, the potential application of TSST-1-induced Tregs also needs to be determined. In this study, a side-by-side comparative study of Tregs induced by TSST-1 and SEA was conducted. Results showed that TSST-1-induced Tregs were different from those induced by SEA in suppressive function, cytokine profile and proliferative ability. Remarkably, TSST-1-induced Tregs were more potent than SEA-induced Tregs in suppressive activities and proliferative ability in vitro. The possible mechanism of TSST-1-induced Tregs was then investigated. TSST-1-induced Tregs did not induce death of target cells, inhibit the activation of target cells, or cause their target cells to acquire regulatory functions. Supernatants from TSST-1-induced Tregs were not suppressive and blockade of IL-10 by a monoclonal antibody did not reverse the suppression. In contrast, cell contact with target cells was required. In addition, TSST-1-induced Tregs were able to compete with their target cells for IL-2. Finally, the potential therapeutic application of TSST-1-induced Tregs was examined by determining their ability to control acute graft-versus-host disease (aGVHD) in a murine model. Data showed that TSST-1-induced Tregs were able to mediate bystander suppression of aGVHD following re-activation upon administration of TSST-1 post transplant. The Tregs inhibited the production of proinflammatory cytokines triggered by alloresponses, but neither affected the engraftment or expansion of donor T cells nor enhanced the elimination of host APCs. Blockade of IL-10 by in vivo administration of a monoclonal antibody did not reverse the suppression. Finally, although TSST-1-induced Tregs attenuated aGVHD, graft-versus-tumor (GVT) effects were preserved, suggesting that these cells differentially regulate aGVHD versus GVT effects.

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