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© The Rockefeller University Press, 0022-1007/1999/1/253/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 2, January 18, 1999 253-264

Articles

T Cell Receptor (TCR) Antagonism without a Negative Signal: Evidence from T Cell Hybridomas Expressing Two Independent TCRs

Sabine H. Stotz*, Luca Bolliger*, Francis R. Carbone{ddagger}, and Ed Palmer*

From the * Basel Institute for Immunology, 4005 Basel, Switzerland; and the {ddagger} Department of Pathology and Immunology, Monash Medical School, Prahran, Victoria 3181, Australia

Antagonist peptides inhibit T cell responses by an unknown mechanism. By coexpressing two independent T cell receptors (TCRs) on a single T cell hybridoma, we addressed the question of whether antagonist ligands induce a dominant-negative signal that inhibits the function of a second, independent TCR. The two receptors, V{alpha}2Vβ5 and V{alpha}2Vβ10, restricted by H-2Kb and specific for the octameric peptides SIINFEKL and SSIEFARL, respectively, were coexpressed on the same cell. Agonist stimulation demonstrated that the two receptors behaved independently with regard to antigen-induced TCR downregulation and intracellular biochemical signaling. The exposure of one TCR (V{alpha}2Vβ5) to antagonist peptides could not inhibit a second independent TCR (V{alpha}2Vβ10) from responding to its antigen. Thus, our data clearly demonstrate that these antagonist ligands do not generate a dominant-negative signal which affects the responsiveness of the entire cell. In addition, a kinetic analysis showed that even 12 h after engagement with their cognate antigen and 10 h after reaching a steady-state of TCR internalization, T cells were fully inhibited by the addition of antagonist peptides. The window of susceptibility to antagonist ligands correlated exactly with the time required for the responding T cells to commit to interleukin 2 production. The data support a model where antagonist ligands can competitively inhibit antigenic peptides from productively engaging the TCR. This competitive inhibition is effective during the entire commitment period, where sustained TCR engagement is essential for full T cell activation.

Key Words: T cell receptor antagonist • T cell activation • T cell commitment

Address correspondence to E. Palmer, Basel Institute for Immunology, Grenzacherstrasse 487, 4005 Basel, Switzerland. Phone: 41-61-605-1277; Fax: 41-61-605-1364; E-mail: palmer{at}bii.ch

The Basel Institute for Immunology was founded and is supported by F. Hoffman-La Roche Ltd., Basel, Switzerland.

Abbreviations used: HRPO, horseradish peroxidase.


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