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Cutting Edge: TNFR-Shedding by CD4⁺CD25⁺ Regulatory T Cells Inhibits the Induction of Inflammatory Mediators¹

Geertje J. D. van Mierlo^2,*, Hans U. Scherer^2,*, Marjolijn Hameetman^2,*, Mary E. Morgan^*, Roelof Flierman^*,, Tom W. J. Huizinga^* and René E. M. Toes^3,*

^* Department of Rheumatology and Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands

CD4⁺CD25⁺ regulatory T (Treg) cells play an essential role in maintaining tolerance to self and nonself. In several models of T cell-mediated (auto) immunity, Treg cells exert protective effects by the inhibition of pathogenic T cell responses. In addition, Treg cells can modulate T cell-independent inflammation. We now show that CD4⁺CD25⁺ Treg cells are able to shed large amounts of TNFRII. This is paralleled by their ability to inhibit the action of TNF- both in vitro and in vivo. In vivo, Treg cells suppressed IL-6 production in response to LPS injection in mice. In contrast, Treg cells from TNFRII-deficient mice were unable to do so despite their unhampered capacity to suppress T cell proliferation in a conventional in vitro suppression assay. Thus, shedding of TNFRII represents a novel mechanism by which Treg cells can inhibit the action of TNF, a pivotal cytokine driving inflammation.

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 study was supported by Dutch Arthritis Foundation Grant 02-I-402 and by research funding from the European Community FP6 funding project 018661 Autocure. The work of R.E.M.T. was supported by a Vidi Grant from the Netherlands Organization for Scientific Research. H.U.S. was supported by a Pfizer Articulum Fellowship.

² G.J.D.v.M., H.U.S., and M.H. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. René E. M. Toes, Department of Rheumatology, Postal Zone C1-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. E-mail address: R.E.M.Toes{at}lumc.nl

⁴ Abbreviations used in this paper: Treg cell, CD4⁺CD25⁺ regulatory T (cell); KO, knockout; MFI, mean fluorescence intensity; sTNFR, soluble TNF-receptor; Teff, effector T (cell); WT, wild type.

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				J. Wang, T. W. J. Huizinga, and R. E. M. Toes De Novo Generation and Enhanced Suppression of Human CD4+CD25+ Regulatory T Cells by Retinoic Acid J. Immunol., September 15, 2009; 183(6): 4119 - 4126. [Abstract] [Full Text] [PDF]