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* Basic Research Program, SAIC-Frederick,
Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702; and
Institute of Immunology, University of Regensburg, Regensburg, Germany
Although TNF is a major proinflammatory cytokine, increasing evidence indicates that TNF also has immunosuppressive feedback effects. We have demonstrated in this study that, in both resting and activated states, mouse peripheral CD4+CD25+ T regulatory cells (Tregs) expressed remarkably higher surface levels of TNFR2 than CD4+CD25– T effector cells (Teffs). In cocultures of Tregs and Teffs, inhibition of proliferation of Teffs by Tregs was initially transiently abrogated by exposure to TNF, but longer exposure to TNF restored suppressive effects. Cytokine production by Teffs remained continually suppressed by Tregs. The profound anergy of Tregs in response to TCR stimulation was overcome by TNF, which expanded the Treg population. Furthermore, in synergy with IL-2, TNF expanded Tregs even more markedly up-regulated expression of CD25 and FoxP3 and phosphorylation of STAT5, and enhanced the suppressive activity of Tregs. Unlike TNF, IL-1
and IL-6 did not up-regulate FoxP3-expressing Tregs. Furthermore, the number of Tregs increased in wild-type mice, but not in TNFR2–/– mice following sublethal cecal ligation and puncture. Depletion of Tregs significantly decreased mortality following cecal ligation and puncture. Thus, the stimulatory effect of TNF on Tregs resembles the reported costimulatory effects of TNF on Teffs, but is even more pronounced because of the higher expression of TNFR2 by Tregs. Moreover, our study suggests that the slower response of Tregs than Teffs to TNF results in delayed immunosuppressive feedback effects.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in whole or in part by the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. This work was also supported in part by the Intramural Research Program, National Institutes of Health, National Cancer Institute, Center for Cancer Research. This work was supported in part by Grant SFB585 B1 from Deutsche Forschungsgemeinschaft. 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.
2 Address correspondence and reprint requests to Dr. Xin Chen, Basic Research Program, SAIC-Frederick, 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: CLP, cecal ligation and puncture; Teff, CD4+CD25– T effector cell; Treg, CD4+CD25+ T regulatory cell.
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