TNF downmodulates the function of human CD4<sup>+</sup>CD25<sup>hi</sup> T-regulatory cells

Xavier Valencia

Geoffrey Stephens

Raphaela Goldbach-Mansky

Mildred Wilson

Ethan Shevach

Peter 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.

Reprints: Xavier Valencia, 10 Center Dr, Rm 6D44, NIAMS/NIH, Bethesda, MD 20892; e-mail: vog.hin.liam@aicnelavx.

Received 2005 Nov 18; Accepted 2006 Feb 22.

Abstract

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 TGFβ1-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^CD25^{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^CD25^{Tregs and restored their suppressive function. Thus, TNF has a novel action in modulating autoimmunity, by inhibiting CD4}^CD25^{Treg activity. (Blood. 2006;108:253-261)}

Abstract

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Acknowledgments

We thank James Simone for his technical expertise with flow cytometry and sorting and Samantha L. Vogt for her technical assistance.

Acknowledgments

Notes

Prepublished online as Blood First Edition Paper, March 14, 2006; DOI 10.1182/blood-2005-11-4567.

An Inside Blood analysis of this article appears at the front of this issue.

The online version of this article contains a data supplement.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 U.S.C. section 1734.

Notes

Prepublished online as Blood First Edition Paper, March 14, 2006; DOI 10.1182/blood-2005-11-4567.An Inside Blood analysis of this article appears at the front of this issue.

The online version of this article contains a data supplement.

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