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Human CD4⁺CD25⁺Foxp3⁺ Regulatory T Cells Do Not Constitutively Express IL-35

Emilie Bardel^1,*, Frédérique Larousserie^1,*,, Pascaline Charlot-Rabiega^*, Aurore Coulomb-L'Herminé and Odile Devergne^2,*

^* Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, Université Paris Descartes, Paris, France; Service d’Anatomie Pathologique, Assistance Publique Hôpitaux de Paris, Université Paris Descartes, Hôpital Cochin, Paris, France; and Service d’Anatomie Pathologique, Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Paris, France

EBV-induced gene 3 (EBI3) can associate with p28 to form the heterodimeric cytokine IL-27, or with the p35 subunit of IL-12 to form the EBI3/p35 heterodimer, recently named IL-35. In mice, IL-35 has been shown to be constitutively expressed by CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Treg cells) and suggested to contribute to their suppressive activity. In this study, we investigated whether human Treg cells express IL-35. Double-staining analysis of human thymuses showed that neither Foxp3⁺ nor CD25⁺ cells coexpressed EBI3. Similarly, Foxp3⁺ cells present in human lymph nodes, tonsils, spleens, and intestines did not express EBI3. Consistent with these in situ observations, Treg cells purified from blood or tonsils were negative for EBI3 by immunoblotting. Other human T cell subsets, including effector T cells, naive and memory CD4⁺ T cells, CD8⁺ and T cells also did not constitutively express EBI3, which contrasts with IL-35 expression observed in murine CD8⁺ and T cells. Furthermore, although CD3/CD28 stimulation consistently induced low levels of EBI3 in various CD4⁺ T cell subsets, no EBI3 could be detected in CD3/CD28-stimulated Treg cells. RT-PCR analysis showed that, whereas p35 transcripts were detected in both Teff and Treg cells, EBI3 transcripts were detected only in activated Teff cells, but not in resting or activated Treg cells. Thus, in contrast to their murine counterpart, human Treg cells do not express detectable amounts of IL-35.

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 E.B. and F.L. share first authorship.

² Address correspondence and reprint requests to Dr. Odile Devergne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, Hôpital Necker, Bâtiment Sèvres, 161 rue de Sèvres, Paris, France. E-mail address: odile. devergne{at}inserm.fr

³ Abbreviations used in this paper: EBI3, EBV-induced gene 3; Treg cell, regulatory T cell; Teff cell, effector T cell.