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Suppression of Regulatory T Cells by IL-12p40 Homodimer via Nitric Oxide¹

Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612

Regulatory T cells (Tregs) play a pivotal role in the maintenance of homeostasis between immune response and immune tolerance. The transcription factor Foxp3 and the surface protein CD25 are the two key molecules characterizing Tregs. In autoimmune and various other chronic inflammatory diseases, the expression of Foxp3 is severely down-regulated. However, the molecular mechanism underlying the down-regulation of Foxp3 is not understood yet. Because the IL-12p40 homodimer (p40₂) is markedly up-regulated in response to various inflammatory stimuli, the present study was undertaken to explore the role of p40₂ in the regulation of Foxp3 in naive mouse splenocytes. IL-12p40₂ dose-dependently inhibited the expression of Foxp3 and CD25, but not CD4. Interestingly, this inhibition was absent in splenocytes of IL-12Rβ1^–/–, but not IL-12Rβ2^–/–, mice. Moreover, suppression of Foxp3 in wild-type and IL-12Rβ2^–/– splenocytes was accompanied by production of NO. Consistently, L-N⁶-(1-iminoethyl)-lysine hydrochloride, an inhibitor of inducible NO synthase (iNOS), and PTIO, a scavenger of NO, restored the expression of Foxp3 and CD25 in p40₂-stimulated splenocytes, and p40₂ was unable to down-regulate Foxp3 and CD25 in splenocytes from iNOS^–/– mice. Furthermore, NO, but not p40₂, was able to inhibit Foxp3 in purified CD4⁺CD25⁺ T cells in the absence of iNOS-expressing cells. Hence, our results clearly demonstrate that p40₂ induces NO production via IL-12Rβ1 and that NO subsequently suppresses Tregs in naive mouse splenocytes. This study, therefore, delineates an unprecedented biological function of p40₂ in the regulation of Foxp3 via IL-12Rβ1-mediated NO production.

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 study was supported by grants from National Institutes of Health (NS39940 and NS48923).

² Address correspondence and reprint requests to Dr. Kalipada Pahan, Department of Neurological Sciences, Rush University Medical Center, Cohn Research Building, Suite 320, 1735 West Harrison Street, Chicago, IL 60612. E-mail address: Kalipada_Pahan{at}rush.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; iNOS, inducible NO synthase; Treg, regulatory T cell; L-NIL, L-N⁶-(1-iminoethyl)-lysine hydrochloride; MFI, mean fluorescence intensity.