DC-independent TSLP-mediated acute allergic airway inflammation via CD11c+ Interstitial Macrophages

Abstract

Abstract Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine important for the development of type-2 inflammatory responses at mucosal surfaces. In humans, TSLP has been found to be elevated in the lungs of asthmatics, and in mouse models TSLP can promote type-2 airway inflammation. DC have been shown to respond directly to TSLP and subsequently promote the differentiation of Th2 cells. In addition, other lung-resident MHCII-expressing cells, such as Alveolar Macrophages (AM) and Interstitial Macrophages (IM), have been shown to regulate the activation of T cells. We have identified a subset of CD11c-expressing Interstitial Macrophages (CD11cIM) addition to AM and IM, which can directly induce proliferation and differentiation of CD4 T cells in a TSLP-dependent manner. Following exposure to TSLP, these cells are more potent then DC for expansion and Th2 cytokine production of CD4 T cells. More importantly, CD11cIM are necessary and sufficient for the induction of Th2 responses and downstream eosinophilic inflammation in the lungs. These findings indicate a novel unique and critical role for TSLP-signaling on CD11cIM in the development of acute Th2-dependent allergic airway inflammation in pulmonary microenvironment.