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TSLP Conditions the Lung Immune Environment for the Generation of Pathogenic Innate and Antigen-Specific Adaptive Immune Responses¹

Mark B. Headley^*,, Baohua Zhou^,, Weihui X. Shih, Theingi Aye, Michael R. Comeau and Steven F. Ziegler^2,*,

^* Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195; Immunology Program, Benaroya Research Institute, Seattle, WA 98101; Department of Pediatrics, H. B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; and Inflammation Research, Amgen, Seattle, WA 98119

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was partially supported by National Institutes of Health Grants AI44259, AI68731, AI71130; Department of Defense Grant USAMRAA W81XWH-07-0246 (to S.F.Z.); and National Cancer Institute training grant Basic Immunology T32, CA009537 (to M.B.H.).

² Address correspondence and reprint requests to Dr. Steven F. Ziegler, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101. E-mail address: sziegler{at}benaroyaresearch.org

³ Abbreviations used in this paper: AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; TSLP, thymic stromal lymphopoietin; SPC-TSLP, surfactant protein C promoter; i.n., intranasal; PAS, periodic acid Schiff; MSA, mouse serum albumin.

⁴ The online version of this article contains supplemental material.