Published ahead of print on October 8, 2009 Am. J. Respir. Crit. Care Med. 2009, doi:10.1164/rccm.200902-0190OC
Submitted on February 6, 2009 Specific CD8 T Cells in Ige-mediated Allergy Correlate with Allergen Dose and Allergic PhenotypeJuan A Aguilar-Pimentel1,1 Department of Dermatology and Allergy, Biederstein, Technische Universität München, Munich, Germany; Clinical Research Division of Molecular and Clinical Allergotoxicology, Technische Universität München, Munich, Germany, 2 Division of Environmental Dermatology and Allergy TUM/ Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Focus Network Nanoparticles and Health (NanoHealth), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, 3 Institute of Microbiology, Immunology, and Hygiene, Technische Universität München, Munich, Germany; Clinical Cooperation Groups ‘Antigen-Specific Immunotherapy’ and ‘Immune-Monitoring’, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg and Technische Universität München, Munich, Germany, 4 Allergy Research Group, University Medical Center Freiburg, Freiburg, Germany, 5 Institute for Inhalation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, 6 Department of Dermatology and Allergy, Biederstein, Technische Universität München, Munich, Germany; Clinical Research Division of Molecular and Clinical Allergotoxicology, Technische Universität München, Munich, Germany; Division of Environmental Dermatology and Allergy TUM/ Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany, 7 Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany * To whom correspondence should be addressed. 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: 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 (OVA257-264) 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 either low dose or high dose OVA sensitization. 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, while the high dose protocol was characterized by a significant reduction of the allergic phenotype. Using OVA257-264 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 even 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
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