Threshold signaling of human Th0 cells in activation and anergy: modulation of effector function by altered TCR ligand.
Molecular interactions between TCR and its natural ligand, in the presence of costimulatory signals, elicit T cell effector functions, whereas subtle changes in the structure of antigenic peptides may induce only selected T cell effector function including anergy. In this study, we have investigated the immunological activity of an altered TCR ligand (p 2, 28-40A34,36) derived from the immunodominant T cell epitope of the group 2 allergen of house dust mite, in which residues at positions 34 and 36 were substituted by alanine. Elevated IFN-gamma synthesis was induced by equimolar concentrations of the analogue compared with native peptide (p 2, 28-40) and was paralleled by increased down-regulation of cell surface CD3. IL-5 and IL-10 production exhibit the same sensitivity to both peptides, implying that the induction of T cell effector functions are not all proportional to TCR occupancy. Both native peptide and the analogue bound to MHC class II (DRB1*1101) molecules with similar affinities. Furthermore, p 2, 28-40A34,36 induced T cell anergy at lower concentrations than native peptide. During the induction of anergy, TGF-beta production was comparable for both peptides, whereas IL-10 secretion was markedly increased but more so in response to p 2, 28-40A34,36. Membrane expression of costimulatory ligands CD80 and CD86 was similar for native peptide and p 2, 28-40A34,36 and increased in activation, whereas only CD86 was elevated during anergy. The modulation of T cell effector function with altered TCR ligands may have practical applications in reprogramming allergic inflammatory responses through the induction of T cell anergy and/or the promotion of Th1 cytokines.
Verhoef
A
A
Department of Biology, Imperial College of Science, Technology and Medicine, London, United Kingdom.
Lamb
J R
JR
D019943:Amino Acid Substitution / Q000276:immunology; D000818:Animals; D039741:Antigens, Dermatophagoides; D017635:Clonal Anergy / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006023:Glycoproteins / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008925:Mites / Q000276:immunology; D010446:Peptide Fragments / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism
D039741:Antigens, Dermatophagoides; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D015848:Interleukin-5; D008024:Ligands; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma