A novel model for antigen-dependent activation of normal human T cells. Transmembrane signaling by crosslinkage of the CD3/T cell receptor-alpha/beta complex with the cluster determinant 2 antigen.
Transmembrane signaling of normal human T cells was explored with mAbs directed at TCR, CD2, CD4, CD5, or CD8 antigens and highly purified CD4+ T cells and CD8+ T cells. Our experiments explicitly show that: (a) crosslinkage of TCR with the CD2 antigen, and not independent crosslinking of TCR and of CD2 antigen or crosslinking of either protein with the CD4 or CD8 antigen induces significant proliferation independent of co-stimulatory signals (e.g., accessory cells, recombinant lymphokines, or tumor promoter), (b) F(ab')2 fragments of mAb directed at the TCR and F(ab')2 anti-CD2, crosslinked with F(ab')2 fragments of rabbit anti-mouse IgG, promote the proliferation of highly purified T cells, (c) a prompt and sustained increase in intracellular free Ca2+ concentration results from crosslinkage of TCR with the CD2 antigen, (d) T cell proliferation induced by this novel approach is curtailed by EGTA and by direct or competitive inhibitors of PKC, (e) crosslinkage of TCR with the CD2 antigen results in the transcriptional activation and translation of the gene for IL-2 and in the expression of IL-2 receptor alpha (CD25), (f) anti-CD25 mAbs inhibit T cell proliferation initiated by crosslinkage of TCR with the CD2 antigen, and recombinant IL-2 restores the proliferative response. Our first demonstration that crosslinkage of TCR with the CD2 antigen induces proliferation of normal human CD4+ T cells and CD8+ T cells, in addition to revealing a novel activation mechanism utilizable by the two major subsets of T cells, suggest that the CD2 antigen might be targeted for the regulation of antigen-specific T cell immunity (e.g., organ transplantation).
Suthanthiran
M
M
Rogosin Institute, Immunogenetics and Transplantation Center, New York, NY 10021.
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D001483:Base Sequence; D018801:CD2 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens; D002118:Calcium / Q000378:metabolism; D003432:Cross-Linking Reagents; D004247:DNA; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D003432:Cross-Linking Reagents; D007140:Immunoglobulin Fab Fragments; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D004247:DNA; D011493:Protein Kinase C; D002118:Calcium