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IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4⁺ T Lymphocytes¹

Ilaria Peluso^*, Massimo Claudio Fantini^*, Daniele Fina^*, Roberta Caruso^*, Monica Boirivant, Thomas T. MacDonald, Francesco Pallone^* and Giovanni Monteleone^2,*

^* Dipartimento di Medicina Interna, Università Tor Vergata, Rome, Italy; Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanita’, Rome, Italy; and Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, United Kingdom

High expression of IL-21 and/or IL-21R has been described in T cell-mediated inflammatory diseases characterized by defects of counterregulatory mechanisms. CD4⁺CD25⁺ regulatory T cells (Treg) are a T cell subset involved in the control of the immune responses. A diminished ability of these cells to inhibit T cell activation has been documented in immune-inflammatory diseases, raising the possibility that inflammatory stimuli can block the regulatory properties of Treg. We therefore examined whether IL-21 controls CD4⁺CD25⁺ T cell function. We demonstrate in this study that IL-21 markedly enhances the proliferation of human CD4⁺CD25^– T cells and counteracts the suppressive activities of CD4⁺CD25⁺ T cells on CD4⁺CD25^– T cells without affecting the percentage of Foxp3⁺ cells or survival of Treg. Additionally, CD4⁺CD25⁺ T cells induced in the presence of IL-21 maintain the ability to suppress alloresponses. Notably, IL-21 enhances the growth of CD8⁺CD25^– T cells but does not revert the CD4⁺CD25⁺ T cell-mediated suppression of this cell type, indicating that IL-21 makes CD4⁺ T cells resistant to suppression rather than inhibiting CD4⁺CD25⁺ T cell activity. Finally, we show that IL-2, IL-7, and IL-15, but not IL-21, reverse the anergic phenotype of CD4⁺CD25⁺ T cells. Data indicate that IL-21 renders human CD4⁺CD25^– T cells resistant to Treg-mediated suppression and suggest a novel mechanism by which IL-21 could augment T cell-activated responses in human immune-inflammatory diseases.

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 received support from the Fondazione Umberto di Mario, Rome; the Broad Medical Research Program Foundation (Grant IBD-0154R); Ministero dell’ Istruzione, dell’ Università e della Ricerca, Grant 2004065777-004, Italy; and Giuliani SpA, Milan, Italy.

² Address correspondence and reprint requests to Dr. Giovanni Monteleone, Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier, 1, Rome, Italy. E-mail address: Gi.Monteleone{at}Med.uniroma2.it

³ Abbreviations used in this paper: Treg, regulatory T cell; Ann V, annexin V.

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