title: Modification of peptide interaction with MHC creates TCR partial agonists.
abstract: We report the creation of TCR partial agonists by the novel approach of manipulating the interaction between immunogenic peptide and MHC. Amino acids at MHC anchor positions of the I-E(k)-restricted hemoglobin (64-76) and moth cytochrome c (88-103) peptides were exchanged with MHC anchor residues from the low affinity class II invariant chain peptide (CLIP), resulting in antigenic peptides with altered affinity for MHC class II. Several low affinity peptides were identified as TCR partial agonists, as defined by the ability to stimulate cytolytic function but not proliferation. For example, a peptide containing methionine substitutions at positions one and nine of the I-E(k) binding motif acted as a partial agonist for two hemoglobin-reactive T cell clones (PL.17 and 3.L2). The identical MHC anchor substitutions in moth cytochrome c (88-103) also created a partial agonist for a mCC-reactive T cell (A.E7). Thus, peptides containing MHC anchor modifications mediated similar T cell responses regardless of TCR fine specificity or antigen reactivity. This data contrasts with the unique specificity among individual clones demonstrated using traditional altered peptide ligands containing substitutions at TCR contact residues. In conclusion, we demonstrate that altering the MHC anchor residues of the immunogenic peptide can be a powerful method to create TCR partial agonists.
authors.affiliation: Graduate Program in Immunology and Molecular Pathogenesis, Department of Microbiology and Immunology, Emory University, 1510 Clifton Rd. Atlanta, GA 30322, USA.
authors.forename: Kelli R
authors.initials: KR
authors.lastname: Ryan
authors.forename: Lisa K
authors.initials: LK
authors.lastname: McNeil
authors.forename: Chinh
authors.initials: C
authors.lastname: Dao
authors.forename: Peter E
authors.initials: PE
authors.lastname: Jensen
authors.forename: Brian D
authors.initials: BD
authors.lastname: Evavold
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045304:Cytochromes c / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte; D005802:Genes, MHC Class II; D006454:Hemoglobins / Q000235:genetics; D019476:Insect Proteins / Q000235:genetics; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015394:Molecular Structure; D009036:Moths; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D006454:Hemoglobins; D019476:Insect Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D045304:Cytochromes c