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FOXP3 Induced by CD28/B7 Interaction Regulates CD25 and Anergic Phenotype in Human CD4⁺CD25^– T Lymphocytes¹

Department of Cellular and Developmental Biology, University Sapienza of Rome, Rome, Italy

Among the signals necessary to generate CD4⁺CD25⁺FOXP3⁺ T cells from CD4⁺CD25^–FOXP3^– T cells, a pivotal role is played by CD28. However, in humans, it is not known whether CD28 signaling independently of TCR promotes forkhead box protein 3 (FOXP3) expression and regulates CD4⁺CD25⁺FOXP3⁺ T cell functions. To address this issue, starting from our previous experience, we analyzed the unique signals delivered by CD28 following stimulation by its natural ligand B7. Our results show that, in primary CD4⁺CD25^– T cells, CD28 signals independent of TCR-mediated stimulatory pathways are sufficient to induce the transcription of FOXP3 in a small number of CD4⁺CD25^– T cells committed to express FOXP3. These signals are dependent on CD28-derived PI3K/Akt pathways and resistant to cyclosporin A. In addition, we demonstrated that translated FOXP3 was recruited to CD25, Il-2, and Ctla4 target promoters. CD28-mediated FOXP3 expression was transient and correlated with CD25 expression. The presence of FOXP3 in CD28-activated CD4⁺CD25^– T cells correlated with a transient unresponsiveness to antigenic stimuli. The addition of exogenous IL-2 did not influence either FOXP3 or CD25 expression but rescued CD28-activated T cells from apoptosis. Our results, demonstrating that FOXP3 expression driven solely by the CD28/B7 interaction inhibited T cell activation, support the role of CD28 in the regulation of peripheral tolerance and suggest a new mechanism through which it could occur.

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 the Institute Pasteur Fondazione Cenci Bolognetti, University Sapienza of Rome, from the Ministry of Universities and Scientific and Technological Research, and from Agenzia Spaziale Italiana, MOMA project.

² Address correspondence and reprint requests to Dr. Enza Piccolella, Department of Cellular and Developmental Biology, Sapienza University of Rome, Rome, Italy. E-mail address: enza.piccolella{at}uniroma1.it

³ Abbreviations used in this paper: T_reg, regulatory T cell; FOXP3, forkhead box protein 3; ChIP, chromatin immunoprecipitation; TCPK, N-p-tosyl-L-phenylalanine chloromethyl ketone; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; CsA, cyclosporin A; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; MFI, mean fluorescence intensity.