The Journal of Experimental Medicine
IN Cell Analyzer 2000
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© The Rockefeller University Press, 0022-1007/1998/5/1699/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 10, May 18, 1998 1699-1709

Articles

Dissociation of Intracellular Signaling Pathways in Response to Partial Agonist Ligands of the T Cell Receptor

Luan A. Chau*, Jeffrey A. Bluestone§, and Joaquín Madrenas*,{ddagger}

From the * Transplantation and Immunobiology Group, The John P. Robarts Research Institute, and the {ddagger} Departments of Microbiology and Immunology and Medicine, the University of Western Ontario, London, Ontario, Canada N6A 5K8; and the § Committee on Immunology, Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60615

The T cell receptor (TCR) is a versatile receptor able to generate different signals that result in distinct T cell responses. The pattern of early signals is determined by the TCR binding kinetics that control the ability of the ligand to coengage TCR and coreceptor. Coengagement of TCR and CD4 results in an agonist signaling pattern with complete tyrosine phosphorylation of TCR subunits, and recruitment and activation of ZAP-70. In contrast, TCR engagement without CD4 coengagement causes a partial agonist type of signaling, characterized by distinct phosphorylation of TCR subunits and recruitment but no activation of ZAP-70. The pathways triggered by partial agonist signaling are unknown. Here, we show that agonists cause association of active lck and active ZAP-70 with p120-GTPase–activating protein (p120-GAP). These associations follow engagement of CD4 or CD3, respectively. In contrast, partial agonists do not activate lck or ZAP-70, but induce association of p120-GAP with inactive ZAP-70. Despite these differences, both agonist and partial agonist signals activate the mitogen-activated protein kinase (MAPK) pathway. However, MAPK activation by partial agonists is transient, supporting a kinetic, CD4-dependent model for the mechanism of action of variant TCR ligands. Transient MAPK activation may explain some of the responses to TCR partial agonists and antagonists.

Key Words: T cell receptor • partial agonist • signal transduction • mitogen-activated protein kinases • p120-GAP

Address correspondence to J. Madrenas, John P. Robarts Research Institute, Rm. 2-05, PO box 5015, 100 Perth Dr., London, ON, Canada N6A 5K8. Phone: 519-663-5777, Ext. 4242; Fax: 519-663-3789; E-mail: madrenas{at}rri.on.ca

Abbreviations used: ERK, extracellular regulated kinase; MAPK, mitogen-activated protein kinase; p120-GAP, p120-GTPase– activating protein; PCC(81-104), pigeon cytochrome c fragment 81–104; ZAP, {zeta}-associated protein.


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