Induction of anergy in human T helper 0 cells by stimulation with altered T cell antigen receptor ligands
Tsitoura, D.C.; Holter, W.; Cerwenka, A.; Gelder, C.M.; Lamb, J.R.
Journal of Immunology 156(8): 2801-2808
1996
ISSN/ISBN: 0022-1767 PMID: 8609399 Document Number: 459586
CD4+ T cells may become profoundly unresponsive to antigenic restimulation following ligation of TCR by immunogenic peptides bound to MHC class 11 molecules in the absence of costimulation. Furthermore, it has been reported that anergy can he induced as a consequence of engagement of TCR by analogues of antigenic peptides presented by live APCs. In this study, based on resolution of the crystal structure of an influenza virus hemagglutinin (HA) peptide (HA 306-318) bound to HLA-DRB1*0101, we investigated the potential of analogues with amino acid substitutions at those positions predicted to form interactions with TCR to differentially activate and/or anergize HA-specific human ThO cells restricted by DR1 class II molecules. For some analogues altering the affinity of peptide/TCR interactions revealed a direct positive correlation between antigenicity and their ability to induce anergy. Nevertheless, certain HA peptide analogues functioned as partial agonists, which although they failed to stimulate clonal expansion, were capable of rendering the ThO cells unresponsive to immunogenic rechallenge. Furthermore, differences were noticed in the characteristics of the anergic phenotype induced by selected analogues. Restimulation with the native peptide of Tho cells pre-exposed to the HA analogues in the absence of costimulatory signals failed to uncouple IL-4 and IFN-gamma secretion; however, in some instances, dissociation of proliferation from cytokine production was observed. The ability to differentially signal T cells through changing the affinity of peptide/TCR interactions may have implications in the potential use of altered TCR ligands in immunotherapy.