Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy

• Published in: Journal of allergy and clinical immunology Vol. 129; no. 2; pp. 544 - 551.e7
• Main Authors: Wambre, Erik, DeLong, Jonathan H., James, Eddie A., LaFond, Rebecca E., Robinson, David, Kwok, William W.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.02.2012; Elsevier; Elsevier Limited
• Subjects: Adult; Allergens - immunology; Allergies; allergy; Allergy and Immunology; Antigens, Plant - immunology; Biological and medical sciences; CD4; CD4-positive T-lymphocytes; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation; Cytokines; Cytokines - immunology; Desensitization, Immunologic; differentiation stage; ex vivo; functional properties; Fundamental and applied biological sciences. Psychology; Fundamental immunology; hay fever; Humans; immune response; Immunoglobulin E - immunology; Immunopathology; Immunotherapy; interferon-gamma; interleukin-10; Lymphocytes; Medical sciences; Middle Aged; Peptides; peptide–MHC class II tetramer; peripheral tolerance; Physiology; Plant Proteins - immunology; pollen; Pollen - immunology; Rhinitis, Allergic, Seasonal - immunology; Rhinitis, Allergic, Seasonal - therapy; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Skin Tests; Software; Statistical analysis; T cells; vaccination; pollen; pMHCII; allergy; peripheral tolerance; T cells; differentiation stage; CD4; PE; Immunotherapy; peptide–MHC class II tetramer; ex vivo; CRTH2; Foxp3; SIT; Forkhead box P3; Allergen-specific immunotherapy; Peptide–MHC class II; Chemoattractant receptor–homologous molecule expressed on T H2 lymphocytes; Phycoerythrin; Allergy; CD4 T lymphocyte; Prognosis; Peptides; Major histocompatibility system; Class II histocompatibility antigen; Prevention; Immunology; Ex vivo; T-Lymphocyte; Evolution; Pollen; Immunopathology; peptide; Tolerance; Cell differentiation; MHC class II tetramer; Clinical stage; Treatment; Tetramer; Differentiation; Allergen
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2011.08.034

The main obstacle to elucidating the role of CD4+ T cells in allergen-specific immunotherapy (SIT) has been the absence of an adequately sensitive approach to directly characterize rare allergen-specific T cells without introducing substantial phenotypic modifications by means of in vitro amplification. We sought to monitor, in physiological conditions, the allergen-specific CD4+ T cells generated during natural pollen exposure and during allergy vaccination. Alder pollen allergy was used as a model for studying seasonal allergies. Allergen-specific CD4+ T cells were tracked and characterized in 12 subjects with alder pollen allergy, 6 nonallergic subjects, and 9 allergy vaccine–treated subjects by using peptide–MHC class II tetramers. Allergen-specific CD4+ T cells were detected in all of the subjects with alder pollen allergy and nonallergic subjects tested. Pathogenic responses—chemoattractant receptor homologous molecule expressed on TH2 lymphocytes (CRTH2) expression and TH2 cytokine production— are specifically associated with terminally differentiated (CD27−) allergen-specific CD4+ T cells, which dominate in allergic subjects but are absent in nonallergic subjects. In contrast, CD27+ allergen-specific CD4+ T cells are present at low frequencies in both allergic and nonallergic subjects and reflect classical features of the protective immune response with high expression of IL-10 and IFN-γ. Restoration of a protective response during SIT appears to be due to the preferential deletion of pathogenic (CD27−) allergen-specific CD4+ T cells accompanied by IL-10 induction in surviving CD27+ allergen-specific CD4+ T cells. Differentiation stage divides allergen-specific CD4+ T cells into 2 distinct subpopulations with unique functional properties and different fates during SIT.