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A Therapeutic CD4 Monoclonal Antibody Inhibits TCR- Chain Phosphorylation, -Associated Protein of 70-kDa Tyr³¹⁹ Phosphorylation, and TCR Internalization in Primary Human T Cells¹

Susanne Harding^*, Peter Lipp and Denis R. Alexander^2,*

Laboratories of ^* Lymphocyte Signaling and Development and Molecular Signaling, The Babraham Institute, Cambridge, United Kingdom

The molecular mechanisms mediating the inhibitory effects of a humanized CD4 mAb YHB.46 on primary human CD4⁺ T cells were investigated. Preincubation of T cells with soluble YHB.46 caused a general inhibition of TCR-stimulated protein tyrosine phosphorylation events, including a reduction in phosphorylation of p95^vav, linker for activation of T cells, and Src homology 2 domain-containing leukocyte protein of 76-kDa signaling molecules. A marked reduction in activation of the Ras/mitogen-activated protein kinase pathway was also observed. Examination of the earliest initiation events of TCR signal transduction showed that YHB.46 inhibited TCR- chain phosphorylation together with recruitment and tyrosine phosphorylation of the -associated protein of 70-kDa tyrosine kinase, particularly at Tyr³¹⁹, as well as reduced recruitment of p56^lck to the TCR- and -associated protein of 70-kDa complex. These inhibitory events were associated with inhibition of TCR endocytosis. Our results show that the YHB.46 mAb is a powerful inhibitor of the early initiating events of TCR signal transduction.

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