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* Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; and
Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
Vitamin A is established as an important immune regulator, but the mechanisms whereby vitamin A regulates T cell biology are poorly defined. In this study, we show that an active metabolite of vitamin A, all-trans retinoic acid (RA), potently stimulates T cell proliferation by modulating IL-2-mediated signaling downstream of IL-2R and independent of the induction of IL-2. Thus, at concentrations as low as 0.1 nM, RA enhanced the division of normal human T lymphocytes that were simultaneously stimulated with anti-CD3 mAbs and saturating concentrations of IL-2. At the optimal concentration of RA (50 nM), a 3-fold increase in T cell proliferation was observed. The induced proliferation was preceded by increased phosphorylation of the retinoblastoma protein and enhanced G1- to S-phase progression. Interestingly, the promitogenic effect of RA was found to be particularly directed toward increased expression of cyclin D3 at both the mRNA and protein level. Furthermore, the stimulatory effect of RA on cyclin D3 expression as well as on cell proliferation was completely abolished in the presence of the JAK inhibitor AG-490 or blocking IL-2R
mAbs, and RA also enhanced cyclin D3 expression and T cell proliferation in the presence of IL-2 alone. Finally, we showed that the proliferative effect of RA was mimicked by agonists of the retinoic acid receptor (RAR) and completely inhibited by a RAR-selective antagonist. In conclusion, our results indicate that RA, via RAR, stimulates IL-2-induced signaling in a JAK-dependent manner to enhance cyclin D3 expression and thereby promote T cell proliferation.
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 the Norwegian Cancer Society, the Norwegian Research Council, Freia Research Foundation, Jahre Research Foundation, and the Blix Family Legacy.
2 Address correspondence and reprint requests to Dr. Heidi Kiil Blomhoff, Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1112 Blindern, N-0317 Oslo, Norway. E-mail address: h.k.blomhoff{at}basalmed.uio.no
3 Abbreviations used in this paper: RA, all-trans retinoic acid; CDK, cyclin-dependent kinase; CKI, CDK inhibitor; PI, propidium iodide; PKB, protein kinase B; pRB, retinoblastoma protein; RAR, retinoic acid receptor; RXR, retinoid X receptor; TTNPB, 4-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid.
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