title: Nonmitogenic anti-CD3 monoclonal antibodies deliver a partial T cell receptor signal and induce clonal anergy.
abstract: Anti-CD3 monoclonal antibodies (mAbs) are potent immunosuppressive agents used in clinical transplantation. However, the activation-related adverse side effects associated with these mAbs have prompted the development of less toxic nonmitogenic anti-CD3 mAb therapies. At present, the functional and biochemical consequences of T cell exposure to nonmitogenic anti-CD3 is unclear. In this study, we have examined the early signaling events triggered by a nonmitogenic anti-CD3 mAb. Like the mitogenic anti-CD3 mAb, nonnmitogenic anti-CD3 triggered changes in the T cell receptor (TCR) complex, including zeta chain tyrosine phosphorylation and ZAP-70 association. However, unlike the mitogenic anti-CD3 stimulation, nonmitogenic anti-CD3 was ineffective at inducing the highly phosphorylated form of zeta (p23) and tyrosine phosphorylation of the associated ZAP-70 tyrosine kinase. This proximal signaling deficiency correlated with minimal phospholipase Cgamma-1 phosphorylation and failure to mobilize detectable Ca2+. Not only did biochemical signals delivered by nonmitogenic anti-CD3 resemble altered peptide ligand signaling, but exposure of Th1 clones to nonmitogenic anti-CD3 also resulted in functional anergy. Finally, a bispecific anti-CD3 X anti-CD4 F(ab)'2 reconstituted early signal transduction events and induced proliferation, suggesting that defective association of lck with the TCR complex may underlie the observed signaling differences between the mitogenic and nonmitogenic anti-CD3.
authors.affiliation: Ben May Institute for Cancer Research, Department of Pathology, Chicago, Illinois 60637, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Smith
authors.forename: J Y
authors.initials: JY
authors.lastname: Tso
authors.forename: M R
authors.initials: MR
authors.lastname: Clark
authors.forename: M S
authors.initials: MS
authors.lastname: Cole
authors.forename: J A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D017252:CD3 Complex / Q000276:immunology*; D017635:Clonal Anergy; D007165:Immunosuppression Therapy / Q000379:methods; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011940:Receptor Aggregation; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse