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Article

Judith A. Smith^*, J. Yun Tso, Marcus R. Clark, Michael S. Cole, and Jeffrey A. Bluestone^*

From the ^* Ben May Institute for Cancer Research, Committee on Immunology, Department of Pathology; Department of Medicine, University of Chicago, Illinois 60637; and Protein Design Laboratories, Mountain View, California 94043

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, nonmitogenic anti-CD3 triggered changes in the T cell receptor (TCR) complex, including 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 (p23) and tyrosine phosphorylation of the associated ZAP-70 tyrosine kinase. This proximal signaling deficiency correlated with minimal phospholipase C-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.

¹Abbreviations used in this paper: APL, altered peptide ligands; IP₃, inositol– triphosphate; PCC, pigeon cytochrome C; PLC-1, phospholipase C-1.

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