title: Flexibility in T-cell receptor ligand repertoires depends on MHC and T-cell receptor clonotype.
abstract: T-cell receptors (TCR) recognize peptides complexed to self-major histocompatibility complex (MHC) molecules. Recognition of peptide/MHC ligands by the TCR is highly peptide specific. However, certain TCRs can also recognize sequence-related and -unrelated ('mimicry') epitopes presented by homologous MHC molecules. Using two human, human leucocyte antigen-DR1 (HLA-DR1)-restricted T-cell clones specific for HA p307-319, we identified several diverse combinations of peptide-MHC complexes that are functionally equivalent in their ability to trigger T-cell stimulation. These findings demonstrate that a single TCR can productively interact with different peptides complexed to self- as well as non-self-MHC molecules. This extended reactivity is human leucocyte antigen (HLA) allele and TCR clonotype dependent, as the peptide repertoire recognized depends on the presenting HLA-DR molecule and varies among different TCRs that both recognize the HA p307-319/DR1 complex. Importantly, certain peptide analogues can completely change the HLA-restriction pattern of the TCR: T-cell recognition of the wild-type peptide that was absent in the context of a non-self HLA-DR molecule, was restored by complementing substitutions in altered peptide ligands, that could not be presented by the original restriction element. This mechanism may play an important role in allorecognition.
authors.affiliation: Department of Immunohematology and Blood Bank, University Hospital, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Geluk
authors.forename: K E
authors.initials: KE
authors.lastname: van Meijgaarden
authors.forename: T H
authors.initials: TH
authors.lastname: Ottenhoff
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins; D018929:Cell Culture Techniques; D002455:Cell Division / Q000276:immunology; D018834:Chaperonin 60; D018833:Chaperonins / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology*; D015798:HLA-DR1 Antigen / Q000276:immunology; D015802:HLA-DR2 Antigen / Q000276:immunology; D006389:Hemagglutinins, Viral / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001426:Bacterial Proteins; D018834:Chaperonin 60; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D015798:HLA-DR1 Antigen; D015802:HLA-DR2 Antigen; D006389:Hemagglutinins, Viral; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C074119:heat-shock protein 65, Mycobacterium; D018833:Chaperonins