title: Tracking antigen-specific T-cells during clinical tolerance induction in humans.
abstract: Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3-5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets.
authors.affiliation: Medical Research Council Human Immunology Unit, National Institute of Health Research Biomedical Research Centre, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Aamir
authors.initials: A
authors.lastname: Aslam
authors.forename: Hsien
authors.initials: H
authors.lastname: Chan
authors.forename: David A
authors.initials: DA
authors.lastname: Warrell
authors.forename: Siraj
authors.initials: S
authors.lastname: Misbah
authors.forename: Graham S
authors.initials: GS
authors.lastname: Ogg
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000941:Antigens / Q000276:immunology*; D017635:Clonal Anergy; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000941:Antigens; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains