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Blood, 1 July 2006, Vol. 108, No. 1, pp. 253-261. Prepublished online as a Blood First Edition Paper on March 14, 2006; DOI 10.1182/blood-2005-11-4567. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 2005-11-4567v1 108/1/253    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Valencia, X. Articles by Lipsky, P. E. Search for Related Content PubMed PubMed Citation Articles by Valencia, X. Articles by Lipsky, P. E. Related Collections Immunobiology Gene Expression Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY TNF downmodulates the function of human CD4+CD25hi T-regulatory cells Xavier Valencia, Geoffrey Stephens, Raphaela Goldbach-Mansky, Mildred Wilson, Ethan M. Shevach, and Peter E. Lipsky From the Autoimmunity Branch, the Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health (NIAMS/NIH), and the Laboratory of Immunology, The National Institute of Allergy and Infectious Diseases (NIAID)/NIH, Bethesda, MD. CD4+CD25+ T-regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. However, little is known about the exogenous factors that regulate their differentiation and function. Here, we report that TNF inhibits the suppressive function of both naturally occurring CD4+CD25+ Tregs and TGF1-induced CD4+CD25+ T-regulatory cells. The mechanism of this inhibition involves signaling through TNFRII that is constitutively expressed selectively on unstimulated Tregs and that is up-regulated by TNF. TNF-mediated inhibition of suppressive function is related to a decrease in FoxP3 mRNA and protein expression by the Tregs. Notably, CD4+CD25hi Tregs isolated from patients with active rheumatoid arthritis (RA) expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4+ effector T cells in vitro. Treatment with anti-TNF antibody (infliximab) increased FOXP3 mRNA and protein expression by CD4+CD25hi Tregs and restored their suppressive function. Thus, TNF has a novel action in modulating autoimmunity, by inhibiting CD4+CD25+ Treg activity. 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