title: Allergen-specific CTL require perforin expression to suppress allergic airway inflammation.
abstract: Allergen-specific CTL have a protective effect on allergic airway inflammation, a function thought to be mediated by cytokines, especially IFN-γ. However, the contribution of cytotoxic function to this protective effect has not been investigated. We examined the contribution of cytotoxic function to the therapeutic effect of allergen-specific CTL in allergic airway inflammation. We used a murine model of allergic airway inflammation in which mice were sensitized to OVA and then challenged with the same Ag via the intranasal route. CTL were elicited in these mice by immunization with dendritic cells (DC) or by adoptive transfer of in vitro-activated CD8(+) T cells. Hallmark features of allergic asthma, such as infiltration of eosinophils in the bronchoalveolar lavage fluid and mucus production, were assessed. Suppression of allergic airway inflammation by allergen-specific CTL was critically dependent on the expression of perforin, a key component of the cytotoxic machinery. Both perforin-sufficient and perforin-deficient allergen-specific CTL were recovered from the lungs of allergen-sensitized mice and upregulated CD69 expression and secreted the cytokines IFN-γ and TNF-α upon intranasal allergen challenge. However, only perforin-sufficient CTL inhibited eosinophil infiltration in the airway, mucus production, and cytokine accumulation in the bronchoalveolar lavage fluid. Treatment with allergen-specific CTL, but not their perforin-deficient counterparts, was also associated with a decrease in the number of DC in the mediastinal lymph node. Our data suggest that the cytotoxic function of allergen-specific CD8(+) T cells is critical to their ability to moderate allergic airway inflammation.
authors.affiliation: Malaghan Institute of Medical Research, 6012 Wellington, New Zealand.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Enomoto
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hyde
authors.forename: Joel Zhi-Iong
authors.initials: JZ
authors.lastname: Ma
authors.forename: Jianping
authors.initials: J
authors.lastname: Yang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Forbes-Blom
authors.forename: Brett
authors.initials: B
authors.lastname: Delahunt
authors.forename: Graham
authors.initials: G
authors.lastname: Le Gros
authors.forename: Franca
authors.initials: F
authors.lastname: Ronchese
mesh_terms: D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009093:Mucus; D010047:Ovalbumin / Q000276:immunology; D054353:Perforin / Q000096:biosynthesis*; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000503:physiopathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000099192:CD69 Antigens
chemical_list: D000485:Allergens; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007073:Immunoglobulin E; D007371:Interferon-gamma; D037181:Lectins, C-Type; D010047:Ovalbumin; D054353:Perforin; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens