title: Ligation of the V7 molecule on T cells blocks anergy induction through a CD28-independent mechanism.
abstract: Previous studies have demonstrated that a mAb that recognizes the leukocyte surface Ag V7 inhibits TCR/CD3-dependent T cell activation. In the current study, we demonstrate that in addition to inhibiting T cell proliferation and IL-2 production, anti-V7 blocks tyrosine phosphorylation of TCR/CD3-associated substrates. PMA overcomes this effect, and both PMA and exogenous IL-2 overcome anti-V7-mediated inhibition of T cell proliferation and IL-2 production. T cells stimulated with anti-CD3 in the absence of CD28 or V7 ligation become unresponsive (anergic) to restimulation with anti-CD3; T cells primed in the presence of either anti-V7 or anti-CD28 retain their ability to respond to restimulation with anti-CD3. When T cells are primed in the presence of optimal concentrations of anti-V7 and anti-CD28 Abs, they proliferate normally, indicating that the costimulatory signals generated through CD28 dominate the inhibitory signals generated through V7. However, as the anti-CD28 stimulus is diluted, the V7 effect becomes dominant and proliferation is inhibited. Thus, although both anti-V7 and anti-CD28 Abs prevent anergy, they induce distinct, competing intracellular signals. Wortmannin, which blocks phosphoinositol 3-kinase-dependent signaling, has little effect on V7-mediated inhibition, while herbimycin, an inhibitor of tyrosine kinase, synergizes with anti-V7 to inhibit T cell activation. On the basis of these findings, V7-mediated signals appear to inhibit TCR-dependent tyrosine kinases that are required for IL-2 production and cellular proliferation.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, CA 94305, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Soares
authors.forename: A
authors.initials: A
authors.lastname: Rivas
authors.forename: L
authors.initials: L
authors.lastname: Tsavaler
authors.forename: E G
authors.initials: EG
authors.lastname: Engleman
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D016227:Benzoquinones; D018106:CD28 Antigens / Q000502:physiology*; D002470:Cell Survival / Q000276:immunology; D017635:Clonal Anergy; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D009183:Mycotoxins / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000276:immunology; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016227:Benzoquinones; C093213:CD101 antigen, human; D018106:CD28 Antigens; D007376:Interleukin-2; D047029:Lactams, Macrocyclic; D008024:Ligands; D008562:Membrane Glycoproteins; D009183:Mycotoxins; D011809:Quinones; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D017828:Rifabutin; D015759:Ionomycin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate; D000077191:Wortmannin