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* Basic Research Program, SAIC-Frederick, National Cancer Institute-Frederick, Frederick, MD 21702; and
Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702
Compelling evidence has now demonstrated that IL-17-producing CD4 cells (Th17) are a major contributor to autoimmune pathogenesis, whereas CD4+CD25+ T regulatory cells (Treg) play a major role in suppression of autoimmunity. Differentiation of proinflammatory Th17 and immunosuppressive Treg from naive CD4 cells is reciprocally related and contingent upon the cytokine environment. We and others have reported that in vivo administration of pertussis toxin (PTx) reduces the number and function of mouse Treg. In this study, we have shown that supernatants from PTx-treated mouse splenic cells, which contained IL-6 and other proinflammatory cytokines, but not PTx itself, overcame the inhibition of proliferation seen in cocultures of Treg and CD4+CD25– T effector cells. This stimulatory effect could be mimicked by individual inflammatory cytokines such as IL-1
, IL-6, and TNF-
. The combination of these cytokines synergistically stimulated the proliferation of CD4+CD25– T effector cells despite the presence of Treg with a concomitant reduction in the percentage of FoxP3+ cells and generation of IL-17-expressing cells. PTx generated Th17 cells, while inhibiting the differentiation of FoxP+ cells, from naive CD4 cells when cocultured with bone marrow-derived dendritic cells from wild-type mice, but not from IL-6–/– mice. In vivo treatment with PTx induced IL-17-secreting cells in wild-type mice, but not in IL-6–/– mice. Thus, in addition to inhibiting the development of Treg, the immunoadjuvant activity of PTx can be attributable to the generation of IL-6-dependent IL-17-producing CD4 cells.
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1 This work was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. government. This research was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.
2 Address correspondence and reprint requests to Dr. Xin Chen, Basic Research Program, SAIC-Frederick, Inc., Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick, P.O. Box B, Building 560, Room 31-19, Frederick, MD 21702-1201. E-mail address: chenxin{at}mail.nih.gov
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; BMDC, bone marrow-derived dendritic cell; LN, lymph node; PTx, pertussis toxin; PTx-CS, PTx-cultured supernatant; Teff, CD4+CD25– T effector cell; Treg, CD4+CD25+ T regulatory cell; wt, wild type.
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