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The Initial Phase of an Immune Response Functions to Activate Regulatory T Cells¹

William E. O'Gorman^2,*, Hans Dooms^2,4,, Steve H. Thorne, Wilson F. Kuswanto, Erin F. Simonds^*, Peter O. Krutzik^*, Garry P. Nolan^3,* and Abul K. Abbas^3,4,

^* Department of Microbiology and Immunology, Baxter Laboratory in Genetic Pharmacology, Stanford University School of Medicine, Stanford, CA 94305; Department of Pathology, University of California at San Francisco School of Medicine, San Francisco, CA 94143; and Division of Surgical Oncology and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213

An early reaction of CD4⁺ T lymphocytes to Ag is the production of cytokines, notably IL-2. To detect cytokine-dependent responses, naive Ag-specific T cells were stimulated in vivo and the presence of phosphorylated STAT5 molecules was used to identify the cell populations responding to IL-2. Within hours of T cell priming, IL-2-dependent STAT5 phosphorylation occurred primarily in Foxp3⁺ regulatory T cells. In contrast, the Ag-specific T cells received STAT5 signals only after repeated Ag exposure or memory differentiation. Regulatory T cells receiving IL-2 signals proliferated and developed enhanced suppressive activity. These results indicate that one of the earliest events in a T cell response is the activation of endogenous regulatory cells, potentially to prevent autoimmunity.

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 by National Institutes of Health Grants RO1 AI073656 and PO1 AI35297 (to A.K.A.) and RO1 AI065824, P01 AI36535, and National Heart, Lung, and Blood Institute Contract N01-HV-28183 (to G.N.).

² W.E.O. and H.D. contributed equally to this work.

³ G.P.N. and A.K.A. share senior authorship for this paper.

⁴ Address correspondence and reprint requests to Dr. Hans Dooms, University of California at San Francisco School of Medicine, HSW-518, 513 Parnassus Avenue, San Francisco, CA 94143. E-mail address: Hans.Dooms{at}ucsf.edu or Dr. Abul K. Abbas, University of California at San Francisco School of Medicine, M-590, 505 Parnassus Avenue, San Francisco, CA 94143. E-mail address: Abul.Abbas{at}ucsf.edu

⁵ Abbreviations used in this paper: Treg, regulatory T cell; BMDC, bone marrow-derived dendritic cell; SSC, side light scatter; SOCS, suppressor of cytokine signaling.