CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters

doi:10.1073/pnas.0308688101

CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-κB subunits on IL-8 and Bcl-xL gene promoters

^*Department of Cellular and Developmental Biology, University of Rome La Sapienza, 00185 Rome, Italy; and ^†Department of Dermatology, University of Rome Tor Vergata, 00133 Rome, Italy

Edited by Arthur Weiss, University of California School of Medicine, San Francisco, CA (received for review January 2, 2004)

Abstract

CD28 is one of the most important costimulatory receptors necessary for full T lymphocyte activation. The CD28 receptor can enhance T cell antigen receptor (TCR) signals, as well as deliver independent signals. Indeed, CD28 engagement by B7 can generate TCR-independent signals leading to IκB kinase and NF-κB activation. Here we demonstrate that the TCR-independent CD28 signal leads to the selective transcription of survival (Bcl-xL) and inflammatory (IL-8 and B cell activation factor, but not proliferative (IL-2), genes, in a NF-κB-dependent manner. CD28-stimulated T cells actively secrete IL-8, and Bcl-xL up-regulation protects T cells from radiation-induced apoptosis. The transcription of CD28-induced genes is mediated by the specific recruitment of RelA and p52 NF-κB subunits to target promoters. In contrast, p50 and c-Rel, which preferentially bind NF-κB sites on the IL-2 gene promoter after anti-CD3 stimulation, are not involved. Thus, we identify CD28 as a key regulator of genes important for both survival and inflammation.

Footnotes

↵ ‡ To whom correspondence should be addressed at: Department of Cellular and Developmental Biology, University of Rome La Sapienza, Via dei Sardi 70, 00185 Rome, Italy. E-mail: tuosto{at}uniroma1.it.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: TCR, T cell antigen receptor; IKK, IκB kinase; BAFF, B cell activator factor; ChIP, chromatin immunoprecipitation; RE, response element.