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Molecular Mechanisms Underlying Differential Contribution of CD28 Versus Non-CD28 Costimulatory Molecules to IL-2 Promoter Activation¹

Xu-Yu Zhou^*, Yumi Yashiro-Ohtani^*, Masakiyo Nakahira^*, Woong Ryeon Park^*, Ryo Abe, Toshiyuki Hamaoka^*, Mayumi Naramura, Hua Gu and Hiromi Fujiwara^2,*

^* Department of Oncology, Osaka University Graduate School of Medicine, Osaka, Japan; Research Institute for Biological Sciences, Science University of Tokyo, Chiba, Japan; and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20892

T cell costimulation via CD28 and other (non-CD28) costimulatory molecules induces comparable levels of [³H]TdR incorporation, but fundamentally differs in the contribution to IL-2 production. In this study, we investigated the molecular basis underlying the difference between CD28 and non-CD28 costimulation for IL-2 gene expression. Resting T cells from a mutant mouse strain generated by replacing the IL-2 gene with a cDNA encoding green fluorescent protein were stimulated with a low dose of anti-CD3 plus anti-CD28 or anti-non-CD28 (CD5 or CD9) mAbs. CD28 and non-CD28 costimulation capable of inducing potent [³H]TdR uptake resulted in high and marginal levels of green fluorescent protein expression, respectively, indicating their differential IL-2 promoter activation. CD28 costimulation exhibited a time-dependent increase in the binding of transcription factors to the NF-AT and NF-B binding sites and the CD28-responsive element of the IL-2 promoter, whereas non-CD28 costimulation did not. Particularly, a striking difference was observed for the binding of NF-B to CD28-responsive element and the NF-B binding site. Decreased NF-B activation in non-CD28 costimulation resulted from the failure to translocate a critical NF-B member, c-Rel, to the nuclear compartment due to the lack of IB inactivation. These observations suggest that unlike CD28 costimulation, non-CD28 costimulation fails to sustain IL-2 promoter activation and that such a failure is ascribed largely to the defect in the activation of c-Rel/NF-B.

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