Specific immunotherapy modifies allergen-specific CD4+ T-cell responses in an epitope-dependent manner

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 3; pp. 872 - 879.e7
• Main Authors: Wambre, Erik, DeLong, Jonathan H., James, Eddie A., Torres-Chinn, Nadia, Pfützner, Wolfgang, Möbs, Christian, Durham, Stephen R., Till, Stephen J., Robinson, David, Kwok, William W.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.03.2014; Elsevier; Elsevier Limited
• Subjects: Allergens - immunology; Allergies; allergy; Allergy and Immunology; Biological and medical sciences; CD4; CD4-Positive T-Lymphocytes - immunology; Cytokines; Desensitization, Immunologic; epitope; Epitopes, T-Lymphocyte - immunology; ex vivo; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Grasses; Humans; Immune Tolerance; Immunopathology; Immunophenotyping; Immunotherapy; Lymphocytes; Medical sciences; Peptides; peptide–MHC class II tetramer; peripheral tolerance; Phleum - immunology; pollen; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Statistical analysis; T cell receptors; T cells; Th1 Cells - immunology; Th2 Cells - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 7 - analysis; ASIT; pollen; pMHCII; allergy; peripheral tolerance; T cells; CD4; PE; Immunotherapy; peptide–MHC class II tetramer; ex vivo; epitope; TGP; Allergen-specific immunotherapy; Timothy grass pollen; Peptide–MHC class II; Phycoerythrin; Allergy; Immunopathology; CD4 T lymphocyte; Immune response; Antigenic determinant; Peptides; Major histocompatibility system; Class II histocompatibility antigen; Tolerance; Immunology; Treatment; peptide-MHC class II tetramer; Ex vivo; Tetramer; T-Lymphocyte; Pollen; Allergen
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2013.10.054

Understanding the mechanisms by which the immune system induces and controls allergic inflammation at the T-cell epitope level is critical for the design of new allergy vaccine strategies. We sought to characterize allergen-specific T-cell responses linked with allergy or peripheral tolerance and to determine how CD4+ T-cell responses to individual allergen-derived epitopes change over allergen-specific immunotherapy. Timothy grass pollen (TGP) allergy was used as a model for studying grass pollen allergies. The breadth, magnitude, epitope hierarchy, and phenotype of the DR04:01-restricted TGP-specific T-cell responses in 10 subjects with grass pollen allergy, 5 nonatopic subjects, and 6 allergy vaccine–treated subjects was determined by using an ex vivo peptide–MHC class II tetramer approach. CD4+ T cells in allergic subjects are directed to a broad range of TGP epitopes characterized by defined immunodominance hierarchy patterns and with distinct functional profiles that depend on the epitope recognized. Epitopes that are restricted specifically to either TH2 or TH1/TR1 responses were identified. Allergen-specific immunotherapy was associated with preferential deletion of allergen-specific TH2 cells and without a significant change in the frequency of TH1/TR1 cells. Preferential allergen-specific TH2 cell deletion after repeated high-dose antigen stimulation can be another independent mechanism to restore tolerance to allergen during immunotherapy.