CD28 delivers a unique signal leading to the selective recruitment of RelA and p52 NF-kappaB subunits on IL-8 and Bcl-xL gene promoters.
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 IkappaB kinase and NF-kappaB 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-kappaB-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-kappaB subunits to target promoters. In contrast, p50 and c-Rel, which preferentially bind NF-kappaB 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.
Marinari
Barbara
B
Department of Cellular and Developmental Biology, University of Rome La Sapienza, 00185 Rome, Italy.
Costanzo
Antonio
A
Marzano
Valeria
V
Piccolella
Enza
E
Tuosto
Loretta
L
D001483:Base Sequence; D001692:Biological Transport; D018106:CD28 Antigens / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D018106:CD28 Antigens; D017931:DNA Primers; D016209:Interleukin-8; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA; D051020:bcl-X Protein