T cell receptor ligands and methods of using same

Abstract

The present invention concerns TCR ligands with immunomodulatory properties, as well as methods of identifying such ligands and of using such ligands to modulate T cell effector responses.

What is claimed is:  
     
         1 . A TCR ligand which substantially inhibits at least one T cell effector response evoked by fully active peptide-MHC molecule complexes available to responding T cells.  
     
     
         2 . The TCR ligand of    claim 1   , which ligand does not substantially inhibit at least one other T cell effector response evoked by fully active peptide-MHC molecule complexes available to responding T cells.  
     
     
         3 . The TCR ligand of    claim 2   , which ligand-inhibits co-stimulation dependent T cell effector responses evoked by fully active peptide-MHC molecule complexes available to responding T cells and which does not block co-stimulation independent T cell effector responses under the same conditions.  
     
     
         4 . A method of modulating T cell effector response by contacting T cells with the T cell-receptor ligand of    claim 1   .  
     
     
         5 . A method of modulating T cell effector responses by contacting T cells with the TCR ligand of    claim 2   .  
     
     
         6 . A method of modulating T cell effector responses by contacting T cells with the TCR ligand of    claim 3   .  
     
     
         7 . A method of modulating the immune response of a host by administering the TCR ligand of    claim 1    to said host.  
     
     
         8 . A method of modulating the immune response of a host by administering the TCR ligand of    claim 2    to said host.  
     
     
         9 . A method of modulating the immune response of a host by administering the TCR ligand of    claim 3    to said host.  
     
     
         10 . A method of identifying a TCR ligand of    claim 1   , which method comprises contacting T cells with an agonist capable of effecting known T cell effector responses and a candidate TCR ligand and determining whether said candidate TCR ligand substantially inhibits at least one T cell effector response.  
     
     
         11 . A method of identifying a TCR ligand of    claim 2   , which method comprises contacting T cells with an agonist capable of effecting known T cell effector responses and a candidate TCR ligand and determining whether said candidate TCR ligand substantially inhibits at least one T cell effector response while not substantially inhibiting at least one other T cell effector response.  
     
     
         12 . The method of    claim 11   , wherein said T cells are simultaneously contacted with said agonist and said candidate TCR ligand by contacting said T cells with a mixture of said agonist and said candidate TCR ligand.  
     
     
         13 . The method of    claim 12   , wherein said mixture of said agonist and said candidate TCR ligand is formed by contacting MHC molecules with a first peptide to form said agonist and then with a second peptide to form said candidate TCR ligand.  
     
     
         14 . The method of    claim 11   , wherein said T cells are contacted with said agonist and then said T cells and said agonist are contacted with said candidate TCR ligand.  
     
     
         15 . A method of preparing candidate TCR ligands as possible TCR ligands of    claim 1   , which method comprises identifying a peptide which binds to MHC molecules to form a complex which can evoke a T cell effector response, determining which residues of said peptide can be substituted so as not to affect binding to said MHc molecules, determining which of said non-binding-effect residues of said peptide affect recognition of said peptide-MHC molecule complex to T cells, substituting said non-binding-effect/recognition-effect residues of said peptide to form substituted peptides, and screening said substituted peptides to identify those substituted peptide-MHC molecule complexes which have less or distinct agonistic effects as compared to the unsubstituted peptide-MHC molecule complex as candidate TCR ligands.  
     
     
         16 . The method of    claim 15   , which method further comprises contacting T cells with an agonist capable of effecting known T cell effector responses and one of said candidate TCR ligands and determining whether said candidate TCR ligand substantially inhibits at least one T cell effector response.  
     
     
         17 . The method of    claim 16   , which method further comprises determining whether said candidate TCR ligand substantially inhibits at least one T cell effector response while not substantially inhibiting at least one other T cell effector response.