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International Immunology, Vol. 12, No. 4, 505-516, April 2000
© 2000 Japanese Society for Immunology

The CD45 tyrosine phosphatase regulates Campath-1H (CD52)-induced TCR-dependent signal transduction in human T cells

Rosemarie A. Hederer, Christine Guntermann, Nigel Miller, Peter Nagy1, Janos Szollosi1, Sandor Damjanovich1, Geoffrey Hale2 and Denis R. Alexander

Laboratory of Lymphocyte Signalling and Development, Molecular Immunology Programme, The Babraham Institute, Cambridge CB2 4AT, UK
1 Department of Biophysics and Cell Biology, Debrecen University School of Medicine, H-4012 Debrecen, Hungary
2 Therapeutic Antibody Centre, Old Road, Headington, Oxford OX3 7JT, UK

Correspondence to: D. R. Alexander

Campath-1H, a humanized mAb undergoing clinical trials for treatment of leukemia, transplantation and autoimmune diseases, produces substantial lymphocyte depletion in vivo.The antibody binds to CD52, a highly glycosylated molecule attached to the membrane by a glycosylphosphatidylinositol anchor. Cross-linked Campath-1H is known to activate T cells in vitro. We have investigated the molecular basis for these effects by comparing the protein tyrosine phosphorylation signals induced by Campath-1H and the CD3 mAb OKT3 in primary T cells, and in CD45+TCR+, CD45–TCR+ and CD45+TCR– Jurkat subclones transfected with CD52. Our results show that Campath-1H triggers similar tyrosine phosphorylation events as OKT3 in both primary T cells and in the CD45+TCR+ Jurkat sub-clone, albeit at quantitatively lower levels. However, no phospholipase C{gamma}1 activation nor calcium signals were detected in response to CD52 ligation. The CD52-mediated induction of protein tyrosine phosphorylation was absolutely dependent upon the expression of both the TCR and the CD45 phosphotyrosine phosphatase at the cell surface. Cross-linking of Campath-1H was essential for signal transduction in all cells investigated. Fluorescence resonance energy transfer was used to demonstrate CD52 homo-association at the cell surface in Jurkat T cells in a TCR- and CD45-independent manner, and CD52–TCR association in CD45+TCR+ cells. We propose a model to explain the activating effects of Campath-1H in which CD52 mAb cross-linking causes the trapping of TCR polypeptides within molecular complexes at the cell surface, thereby inducing signals via the TCR by a process which depends on the CD45-mediated regulation of the p56lck and p59fyn tyrosine kinases.

Keywords: Campath-1H, CD45, CD52, transduction

Transmitting editor: P. Beverley


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