Thymic Stromal Lymphopoietin: Expression and Secretion by Airway Epithelium as a Function of Genotype

Abstract

Thymic stromal lymphopoietin (TSLP) is a pleotropic cytokine highly implicated in the pathophysiology of asthma and allergic diseases. Although there are robust data regarding the associations of TSLP polymorphisms with the development of allergy and asthma, there is very little information on how these TSLP variants functionally affect downstream effector pathways and disease phenotype. The overall objective of this thesis was to investigate how TSLP polymorphisms are linked to alterations in TSLP secretion and subsequent downstream cellular events. Initially, we investigated the influence of innate and adaptive stimuli on epithelial-derived TSLP expression and secretion, including effects on dendritic cells (DC). We show that polyinosinic:polycytidylic acid (polyI:C) and allergen-specific T cells induced enhanced TSLP secretion from asthmatic bronchial epithelial cells (BEC) compared to non-asthmatic BEC. Furthermore, activated-BEC culture supernatants induced TSLP-dependent CCL17 production from monocyte-derived DC in relation to clinical asthmatic status (Chapter 2). Next, we examined effects of TSLP on hemopoietic progenitor eosinophil-basophil (Eo/B) differentiation, demonstrating enhanced TSLP-mediated hemopoiesis ex vivo in relation to clinical atopic status. We further demonstrated p38MAPK-dependent autocrine signaling by TNFα in TSLP-mediated human Eo/B differentiation ex vivo (Chapter 3). Lastly, to explore the potential functional consequences of a key variant of the TSLP gene, we investigated associations between the rs1837253 TSLP variant and ex vivo production of TSLP in nasal epithelial cells (NEC). We showed that NEC derived from individuals with the “protective” minor allele have diminished TSLP secretion, which suggests that this rs1837253 polymorphism may be directly involved in the regulation of TSLP secretion (Chapter 4). The novel work presented herein provides further evidence for TSLP regulation of distinct immunological pathways in allergic immune inflammatory airway responses initiated at the epithelial surface, and thus (by implication) of allergic disease. These observations support the concept that TSLP is potentially an important biomarker and therapeutic target for allergic diseases characterized by increased Th2 and/or eosinophilic-basophilic inflammation. Continued investigations into the functional mechanisms linking TSLP variants to allergic disease phenotype are of critical importance.