Open AccessA Therapeutic CD4 Monoclonal Antibody Inhibits TCR-ζ Chain Phosphorylation, ζ-Associated Protein of 70-kDa Tyr319 Phosphorylation, and TCR Internalization in Primary Human T Cells
Author(s) -
Susanne Harding,
Peter Lipp,
Denis R. Alexander
Publication year - 2002
Publication title -
the journal of immunology/the journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.737
H-Index - 372
eISSN - 1550-6606
pISSN - 0022-1767
DOI - 10.4049/jimmunol.169.1.230
Subject(s) - t cell receptor , phosphorylation , tyrosine phosphorylation , internalization , biology , microbiology and biotechnology , signal transduction , cd3 , tyrosine kinase , proto oncogene tyrosine protein kinase src , tyrosine , protein kinase a , t cell , biochemistry , receptor , cd8 , antigen , immune system , immunology
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-zeta chain phosphorylation together with recruitment and tyrosine phosphorylation of the zeta-associated protein of 70-kDa tyrosine kinase, particularly at Tyr(319), as well as reduced recruitment of p56(lck) to the TCR-zeta and zeta-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.