Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation.
Optimal activation of T cells requires effective occupancy of both the antigen-specific T cell receptor and a second coreceptor such as CD28. We used cDNA microarrays to characterize the genomic expression program in human peripheral T cells responding to stimulation of these receptors. We found that CD28 agonists alone elicited few, but reproducible, changes in gene expression, whereas CD3 agonists elicited a multifaceted temporally choreographed gene expression program. The principal effect of simultaneous engagement of CD28 was to increase the amplitude of the CD3 transcriptional response. The induced genes whose expression was most enhanced by costimulation were significantly enriched for known targets of nuclear factor of activated T cells (NFAT) transcription factors. This enhancement was nearly abolished by blocking the nuclear translocation of NFATc by using the calcineurin inhibitor FK506. CD28 signaling promoted phosphorylation, and thus inactivation, of the NFAT nuclear export kinase glycogen synthase kinase-3 (GSK3), coincident with enhanced dephosphorylation of NFATc proteins. These results provide a detailed picture of the transcriptional program of T cell activation and suggest that enhancement of transcriptional activation by NFAT, through inhibition of its nuclear export, plays a key role in mediating the CD28 costimulatory signal.
Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
Maximilian
M
Diehn
Ash A
AA
Alizadeh
Oliver J
OJ
Rando
Chih Long
CL
Liu
Kryn
K
Stankunas
David
D
Botstein
Gerald R
GR
Crabtree
Patrick O
PO
Brown
D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D021381:Protein Transport; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism
D018106:CD28 Antigens; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors