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Specific CD8 T Cells in IgE-mediated Allergy Correlate with Allergen Dose and Allergic Phenotype

¹ Department of Dermatology and Allergy, Biederstein, Technische Universität München, and Clinical Research Division of Molecular and Clinical Allergotoxicology, Technische Universität München, Munich; ² Division of Environmental Dermatology and Allergy TUM/ Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; ³ Focus Network Nanoparticles and Health (NanoHealth), Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg; ⁴ Institute of Microbiology, Immunology, and Hygiene, Technische Universität München, Munich; ⁵ Clinical Cooperation Groups ‘Antigen-Specific Immunotherapy’ and ‘Immune-Monitoring’, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg and Technische Universität München, Munich; ⁶ Allergy Research Group, University Medical Center Freiburg, Freiburg; ⁷ Institute for Inhalation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; and ⁸ Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

Correspondence and requests for reprints should be addressed to Prof. Markus Ollert, M.D., Department of Dermatology and Allergy, Biederstein Technische Universität München Biedersteiner Str. 29 D-80802 München, Germany. E-mail: ollert{at}lrz.tum.de

Rationale: Studies in humans and rodents have indicated a causative role for CD8⁺ T cells in IgE-mediated allergic inflammation, but their function is still controversial.

Objectives: To analyze the role of allergen-specific CD8⁺ T cells during the development of allergic airway inflammation in two parallel but diverging outcome models.

Methods: We used H2-Kb SIINFEKL (OVA_257–264) multimers to analyze induction, natural distribution, and phenotype of allergen-specific CD8⁺ T cells in a murine C57BL/6 model of ovalbumin (OVA)-induced allergic airway inflammation using low-dose or high-dose OVA sensitization.

Measurements and Main Results: The low-dose protocol was characterized by a significant induction of total and OVA-specific IgE, eosinophilic airway inflammation, IL-4 levels in bronchoalveolar lavage fluid. And significant alterations in lung function. The high dose protocol was characterized by a significant reduction of the allergic phenotype. Using OVA_257–264 H2-Kb multimers, we observed lung and airway infiltrating OVA-specific CD8⁺ T cells showing an effector/effector-memory phenotype. The high-dose protocol caused significantly higher infiltration of allergen-specific CD8⁺ cells to the airways and enhanced their cytotoxicity. Adoptive transfer with CD8⁺ T cells from transgenic OT-I mice to TAP1^–/– or wild-type mice showed their migration to the lungs and TAP1-dependent proliferation after OVA-aerosol exposure. TAP1^–/– mice defective in CD8⁺ T cells showed exacerbated symptoms in the low-dose sensitization model.

Conclusions: Allergen-specific CD8⁺ T cells seem to protect from allergic inflammation in the lungs. Their number, which is dependent on the sensitization dose, appears to be a critical predictor for the severity of the allergic phenotype.

Key Words: cytotoxicity • tolerance • airway inflammation • asthma • immunotherapy

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Previous studies have indicated a divergent role for specific CD8+ T cells in allergic airway disease. To address this controversy, opposing priming conditions for CD8+ T cells using high- or low-dose allergen concentrations were applied. What This Study Adds to the Field The recruitment of functionally active allergen-specific CD8+ T cells to the airways, which is dependent on the allergen sensitization dose, appears to be a critical predictor for the severity of the allergic phenotype in mice.