Molecular mechanisms underlying differential contribution of CD28 versus non-CD28 costimulatory molecules to IL-2 promoter activation

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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3847-3854
Number of pages8
JournalJournal of Immunology
Volume168
Issue number8
DOIs
StatePublished - Apr 15 2002

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Interleukin-2
Green Fluorescent Proteins
Mutant Strains Mice
Binding Sites
NFATC Transcription Factors
T-Lymphocytes
Complementary DNA
Gene Expression
Genes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Molecular mechanisms underlying differential contribution of CD28 versus non-CD28 costimulatory molecules to IL-2 promoter activation. / Zhou, Xu Yu; Yashiro-Ohtani, Yumi; Nakahira, Masakiyo; Park, Woong Ryeon; Abe, Ryo; Hamaoka, Toshiyuki; Naramura, Mayumi; Gu, Hua; Fujiwara, Hiromi.

In: Journal of Immunology, Vol. 168, No. 8, 15.04.2002, p. 3847-3854.

Research output: Contribution to journalArticle

Zhou, XY, Yashiro-Ohtani, Y, Nakahira, M, Park, WR, Abe, R, Hamaoka, T, Naramura, M, Gu, H & Fujiwara, H 2002, 'Molecular mechanisms underlying differential contribution of CD28 versus non-CD28 costimulatory molecules to IL-2 promoter activation', Journal of Immunology, vol. 168, no. 8, pp. 3847-3854. https://doi.org/10.4049/jimmunol.168.8.3847
Zhou, Xu Yu ; Yashiro-Ohtani, Yumi ; Nakahira, Masakiyo ; Park, Woong Ryeon ; Abe, Ryo ; Hamaoka, Toshiyuki ; Naramura, Mayumi ; Gu, Hua ; Fujiwara, Hiromi. / Molecular mechanisms underlying differential contribution of CD28 versus non-CD28 costimulatory molecules to IL-2 promoter activation. In: Journal of Immunology. 2002 ; Vol. 168, No. 8. pp. 3847-3854.
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