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Distinct Molecular Program Imposed on CD4⁺ T Cell Targets by CD4⁺CD25⁺ Regulatory T Cells¹

Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Rochester, Rochester, NY 14642

CD4⁺CD25⁺ regulatory T cells (Tregs) are key modulators of immunity, but their mechanism of action is unclear. To elucidate the molecular consequences of Treg encounter, we analyzed changes in gene expression in CD4⁺ T cell targets activated in the presence or absence of CD4⁺CD25⁺ Tregs. Tregs did not alter the early activation program of CD4⁺ T cells, but had reversed many of the activation-induced changes by 36 h. It is not known whether Tregs simply induce a set of transcriptional changes common to other nonproliferative states or whether instead Tregs mediate a distinct biological activity. Therefore, we compared the gene profile of T cells following Treg encounter with that of T cells made anergic, TGF-β-treated, or IL-2-deprived; all possible modes of Treg action. Strikingly, all genes down-regulated in suppressed cells were indeed common to these nonproliferative states. In contrast, Treg encounter led to elevated expression of a unique set of genes in the target T cells. Although different from the nonproliferative states tested, the Treg-imposed gene program is exemplified by expression of many genes associated with growth arrest or inhibition of proliferation. We suggest that Tregs function by the induction of a distinct set of negative regulatory factors that initiate or maintain target T cells in a nonproliferative state.

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 the Juvenile Diabetes Research Foundation, Research Grant 1-2000-609 (to D.J.F.) and National Institutes of Health Training Grant AI-07169 (to T.L.S.).

² Address correspondence and reprint requests to Dr. Deborah J. Fowell, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology and Immunology, University of Rochester, 601 Elmwood Avenue, Box 609, Rochester, NY 14642. E-mail address: deborah_fowell{at}urmc.rochester.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; 7-AAD, 7-aminoactinomycin D; KLF, Kruppel family; GRP1, general receptor of phosphoinositide 1.

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