Portal de Periódicos da CAPES

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

2002; American Association of Immunologists; Volume: 168; Issue: 8 Linguagem: Inglês

10.4049/jimmunol.168.8.3847

1550-6606

Xuyu Zhou, Yumi Yashiro–Ohtani, Masakiyo Nakahira, Woong Ryeon Park, Ryo Abe, Toshiyuki Hamaoka, Mayumi Naramura, Hua Gu, Hiromi Fujiwara,

Immune Response and Inflammation

Abstract 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-κB 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-κB to CD28-responsive element and the NF-κB binding site. Decreased NF-κB activation in non-CD28 costimulation resulted from the failure to translocate a critical NF-κB member, c-Rel, to the nuclear compartment due to the lack of IκBβ 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-κB.