Synergism between the CD3 antigen- and CD2 antigen-derived signals. Exploration at the level of induction of DNA-binding proteins and characterization of the inhibitory activity of cyclosporine.
We have demonstrated earlier that the crosslinkage of the CD3/TCR complex with the CD2 antigen results in the proliferation of normal human T cells. The effect of this synergism was perceptible at the level of induction of the IL-2 gene, a process critical for T cell growth. To further understand the molecular and nuclear basis for this synergism, we have explored the induction of DNA-binding proteins in highly purified normal human T cells signaled via the CD3 and/or CD2 proteins. The effect of transmembrane signaling of T cells with ionomycin, and/or sn-1,2 dioctanoyl glycerol, was also determined. The emergence of nuclear binding proteins was investigated using interleukin-2 sequence specific oligonucleotide probes in the electrophoretic mobility shift assay. Our studies demonstrate for the first time that CD3 antigen-derived signals and CD2 antigen-derived signals are synergistic in inducing the emergence of transcription factors that bind to the NF-AT1, AP-1, and NF-kB sites located in the promoter/enhancer region of the IL-2 gene. Moreover, cyclosporine, at concentrations readily accomplished in clinical practice, was found to inhibit the emergence of these DNA-binding proteins in normal human T cells signaled via cell surface proteins implicated in antigen-dependent T cell activation and in T cells stimulated by mobilization of cellular calcium and activation of protein kinase C.
Sehajpal
P K
PK
Iris and B. Gerald Cantor Laboratory for Immunological Research in Diabetes, Immunogenetics and Transplantation Center, Rogosin Institute, New York, NY 10021.
Sharma
V K
VK
Ingulli
E
E
Stenzel
K H
KH
Suthanthiran
M
M
D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D001483:Base Sequence; D018801:CD2 Antigens; D017252:CD3 Complex / Q000502:physiology*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D016572:Cyclosporine / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000737:chemistry
D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D017252:CD3 Complex; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D011971:Receptors, Immunologic; D016572:Cyclosporine