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Effective Proliferation of Human Regulatory T Cells Requires a Strong Costimulatory CD28 Signal That Cannot Be Substituted by IL-2¹

Zentrum für Molekulare Medizin Köln and Klinik I für Innere Medizin, Labor Tumorgenetik, Universität zu Köln, Köln, Germany

The strength of immune repression by regulatory T (Treg) cells is thought to depend on the efficiency of Treg cell activation. The stimuli and their individual strength required to activate resting human Treg cells, however, have so far not been elucidated in detail. We reveal here that induction of proliferation of human CD4⁺C25⁺ Treg cells requires an extraordinary strong CD28 costimulatory signal in addition to TCR/CD3 engagement. CD28 costimulation, noteworthy, cannot be substituted by IL-2 to induce proliferation of Treg cells, which is in contrast to CD4⁺CD25^– T cells. IL-2, in contrast, prevents spontaneous apoptosis of Treg cells, but does not initiate their amplification. IL-2 and CD28 costimulation clearly exhibit disparate effects on Treg cells which are in contrast to those on CD4⁺CD25^– T cells. Moreover, the prerequisites for Treg cell proliferation differ strikingly from those for effector T cells, implying a balanced orchestration in initiating and limiting a T cell immune response. In addition, data are of relevance for the design of therapeutic strategies involving IL-2 administration and CD28 costimulation.

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 grants from Deutsche Krebshilfe, Deutsche Forschungsgemeinschaft, Wilhelm Sander-Stiftung, Fortune program of the Medical Faculty of the University of Cologne, and European Commission through the ATTACK project.

² Address correspondence and reprint requests to Dr. Andreas Hombach, Klinik I für Innere Medizin, Labor für Tumorgenetik, Universität zu Köln, Kerpener Strasse 62, D-50924 Köln, Germany. E-mail address: andreas.hombach{at}uk-koeln.de

³ Abbreviation used in this paper: Treg, regulatory T cell.

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