THE EFFICIENCY OF CD4 RECRUITMENT TO LIGAND-ENGAGED TCR CONTROLS THE AGONIST PARTIAL AGONIST PROPERTIES OF PEPTIDE-MHC MOLECULE LIGANDS/

One hypothesis seeking to explain the signaling and biological propert ies of T cell receptor for antigen (TCR) partial agonists and antagoni sts is the coreceptor density/kinetic model, which proposes that the p harmacologic behavior of a TCR ligand is largely determined by the rel ative 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 interact ion is to convert typical agonists into partial agonist stimuli. Thus, adding anti-CD4 antibody to T cells recognizing a wild-type peptide-M HC class II ligand leads to disproportionate inhibition of interleukin -2 (IL-2) relative to IL-3 production, the same pattern seen using a T CR partial agonist/antagonist. In addition, T cells exposed to wild-ty pe ligand in the presence of anti-CD4 antibodies show a pattern of TCR signaling resembling that seen using partial agonists, with predomina nt accumulation of the p 21 tyrosine-phosphorylated form of TCR-zeta, reduced tyrosine phosphorylation of CD3 epsilon, and no detectable pho sphorylation of ZAP-70. Similar results are obtained when the wild-typ e Ligand is presented by mutant class II MHC molecules unable to bind CD4. Likewise, antibody coligation of CD3 and CD4 results in an agonis t-like phosphorylation pattern, whereas bivalent engagement of CD3 alo ne 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 an d functional responses to variant TCR ligands with partial agonist pro perties can be largely reproduced by inhibiting recruitment of CD4 to a TCR binding a wild-type ligand, consistent with the idea that the re lative rates of TCR-ligand disengagement and of association of engaged TCR with CD4 may play a key role in determining the pharmacologic pro perties of peptide-MHC molecule ligands. Beyond this insight into sign aling through the TCR, these results have implications for models of t hymocyte selection and the use of anti-coreceptor antibodies in vivo f or the establishment of immunological tolerance.