title: Signal transduction pathways involved in T cell receptor-induced regulation of CD2 avidity for CD58.
abstract: Through physiologic interactions with its ligands CD58 (lymphocyte function-associated Ag-3, LFA-3) and CD59, the T cell glycoprotein CD2 plays a role in T cell signaling and promotes lymphocyte adhesion. We have recently demonstrated that the interaction of CD2 with CD58 is dynamic: TCR stimulation or treatment with the phorbol ester PMA rapidly up-regulates CD2 ligand avidity, and this regulation requires the carboxyl-terminal asparagine residue of the CD2 cytoplasmic domain. Here we have analyzed the regulation of CD2 avidity for CD58, as assessed by the binding of CD2+ cells to purified CD58 and by the formation of rosettes between CD2+ cells and SRBC. In murine T cell hybridomas transfected with human CD2, we show that, unlike CD2-mediated IL-2 production, cell surface expression of the TCR-CD3 structure is not required for up-regulation of CD2 ligand avidity. TCR-initiated up-regulation of CD2 avidity requires the activity of both protein tyrosine kinases and protein kinase C. Agents which elevate intracellular levels of cAMP also up-regulate CD2 ligand avidity and act either distal to or independently of protein kinase C and protein tyrosine kinases. Cell lines expressing single amino acid substitutions of the carboxyl-terminal asparagine of CD2 are incapable of avidity regulation by TCR signaling, PMA treatment, or elevation of intracellular cAMP levels, demonstrating that each of these stimuli utilizes a common structural element for regulating CD2 avidity. The response to both cAMP and phorbol ester treatment distinguishes the regulation of CD2 avidity from that of a second major adhesion pathway, LFA-1 (CD11a/CD18)/ICAM-1 (CD54) and from that of the TCR coreceptor CD8. These observations identify the signaling events involved in the regulation of CD2 avidity and help to define the signal transduction processes that participate in "inside-out" signaling.
authors.affiliation: Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: W C
authors.initials: WC
authors.lastname: Hahn
authors.forename: S J
authors.initials: SJ
authors.lastname: Burakoff
authors.forename: B E
authors.initials: BE
authors.lastname: Bierer
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects / Q000378:metabolism*; D003994:Bucladesine / Q000494:pharmacology; D018801:CD2 Antigens; D018968:CD58 Antigens; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism*; D012397:Rosette Formation; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018801:CD2 Antigens; D018968:CD58 Antigens; D008562:Membrane Glycoproteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate