title: TSLP conditions the lung immune environment for the generation of pathogenic innate and antigen-specific adaptive immune responses.
abstract: Thymic stromal lymphopoietin (TSLP) is crucial for the development of atopic diseases in humans and mice. Mice that express a lung-specific TSLP transgene (surfactant protein C promoter (SPC)-TSLP) develop a spontaneous and progressive asthma-like disease, suggesting that TSLP expression alone was sufficient for disease development. In this study, we show that, in fact, TSLP alone only causes a weak innate response that is insufficient for development of full airway inflammatory disease. Complete disease development requires both TSLP and antigenic stimulation. These data suggest that the spontaneous lung inflammation observed in SPC-TSLP mice reflects a TSLP-driven predisposition toward the development of aberrant responses against innocuous environmental Ags. This provides evidence that TSLP may act directly to induce susceptibility to the inappropriate allergic responses that characterize atopy and asthma. We additionally show that disease development requires CD4 T cells but not B cells. Further, we reveal a TSLP-driven innate response involving mucus overproduction and goblet cell metaplasia. Taken together, these data suggest a multifaceted model of TSLP-mediated airway inflammation, with an initial activation of resident innate immune cells, followed by activation of the adaptive immune system and full disease development. This study provides new insight into the unique features of the asthma pathology contributed by the innate and adaptive immune responses in response to TSLP stimulation.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Headley
authors.forename: Baohua
authors.initials: B
authors.lastname: Zhou
authors.forename: Weihui X
authors.initials: WX
authors.lastname: Shih
authors.forename: Theingi
authors.initials: T
authors.lastname: Aye
authors.forename: Michael R
authors.initials: MR
authors.lastname: Comeau
authors.forename: Steven F
authors.initials: SF
authors.lastname: Ziegler
mesh_terms: D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000008:administration & dosage* / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D000939:Epitopes / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006969:Hypersensitivity, Immediate / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate / Q000235:genetics; D016130:Immunophenotyping; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D000939:Epitopes; D037721:Pulmonary Surfactant-Associated Protein C; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse