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From the * Transplantation and Immunobiology Group, The John P. Robarts Research Institute; the One hypothesis seeking to explain the signaling and biological properties of T cell receptor for
antigen (TCR) partial agonists and antagonists is the coreceptor density/kinetic model, which proposes that the pharmacologic behavior of a TCR ligand is largely determined by the relative
rates of (a) dissociation of ligand from an engaged TCR and (b) recruitment of lck-linked coreceptors to this ligand-engaged receptor. Using several approaches to prevent or reduce the association of CD4 with occupied TCR, we demonstrate that consistent with this hypothesis,
the biological and biochemical consequence of limiting this interaction is to convert typical agonists into partial agonist stimuli. Thus, adding anti-CD4 antibody to T cells recognizing a
wild-type peptide-MHC class II ligand leads to disproportionate inhibition of interleukin-2
(IL-2) relative to IL-3 production, the same pattern seen using a TCR partial agonist/antagonist. In addition, T cells exposed to wild-type ligand in the presence of anti-CD4 antibodies
show a pattern of TCR signaling resembling that seen using partial agonists, with predominant
accumulation of the p21 tyrosine-phosphorylated form of TCR- Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario,
Canada; the § Committee on Immunology, Ben May Institute for Cancer Research, University of
Chicago, Chicago, Illinois 60615; and the Lymphocyte Biology Section, Laboratory of Immunology,
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda,
Maryland 20892-1892
, reduced tyrosine phosphorylation of CD3
, and no detectable phosphorylation of ZAP-70. Similar results are obtained
when the wild-type ligand is presented by mutant class II MHC molecules unable to bind
CD4. Likewise, antibody coligation of CD3 and CD4 results in an agonist-like phosphorylation pattern, whereas bivalent engagement of CD3 alone gives a partial agonist-like pattern. Finally, in accord with data showing that partial agonists often induce T cell anergy, CD4 blockade during antigen exposure renders cloned T cells unable to produce IL-2 upon restimulation.
These results demonstrate that the biochemical and functional responses to variant TCR
ligands with partial agonist properties can be largely reproduced by inhibiting recruitment of
CD4 to a TCR binding a wild-type ligand, consistent with the idea that the relative rates of
TCR-ligand disengagement and of association of engaged TCR with CD4 may play a key role
in determining the pharmacologic properties of peptide-MHC molecule ligands. Beyond this
insight into signaling through the TCR, these results have implications for models of thymocyte selection and the use of anti-coreceptor antibodies in vivo for the establishment of immunological tolerance.
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