TSLP drives acute TH2-cell differentiation in lungs
Authors: Jen-Feng Lai, Lucas J. Thompson, Steven F. Ziegler
Journal: Journal of Allergy and Clinical Immunology (2020)

BackgroundThymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine that is important for the development of type 2 inflammatory responses at mucosal surfaces.ObjectiveIn humans, TSLP level has been found to be elevated in the lungs of patients with asthma, and in mouse models, TSLP can promote type 2 airway inflammation, primarily through the activation of dendritic cells. However, the mechanisms underlying its role remain unclear. The objective of this study was to provide a mechanistic analysis of TSLP-mediated type 2 airway inflammationMethodsTo dissect the mechanisms of TSLP-mediated type 2 responses, mice were treated with TSLP and antigen to evaluate cellular immune responses. Flow cytometric analyses were used to follow responses in the airways, and conditional deletion of TSLP receptor and adoptive transfer were used to identify the cellular subsets involved in this inflammatory response.ResultsWe showed that TSLP can directly promote TH2-cell differentiation in the lung, independent of the draining lymph nodes. We also identified a population of patrolling monocytes/interstitial macrophages (IMs) (CD11c-expressing IMs) that are both necessary and sufficient for TSLP-mediated TH2-cell differentiation and airway inflammation. TH2-cell–driven airway eosinophilia is attenuated by ablation of CD11c-expressing IMs or by selective deficiency of TSLP receptor signaling in these cells. More importantly, CD11c-expressing IMs are sufficient for the induction of acute TH2-cell responses in the lungs that is independent of dendritic cells and T-cell priming in the draining lymph nodes.ConclusionThese findings indicate a novel mechanistic role for TSLP and CD11c-expressing IMs in the development of acute TH2-cell–dependent allergic airway inflammation. This work also demonstrates a new role for TSLP in promoting type 2 responses directly in the lung. Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine that is important for the development of type 2 inflammatory responses at mucosal surfaces. In humans, TSLP level has been found to be elevated in the lungs of patients with asthma, and in mouse models, TSLP can promote type 2 airway inflammation, primarily through the activation of dendritic cells. However, the mechanisms underlying its role remain unclear. The objective of this study was to provide a mechanistic analysis of TSLP-mediated type 2 airway inflammation To dissect the mechanisms of TSLP-mediated type 2 responses, mice were treated with TSLP and antigen to evaluate cellular immune responses. Flow cytometric analyses were used to follow responses in the airways, and conditional deletion of TSLP receptor and adoptive transfer were used to identify the cellular subsets involved in this inflammatory response. We showed that TSLP can directly promote TH2-cell differentiation in the lung, independent of the draining lymph nodes. We also identified a population of patrolling monocytes/interstitial macrophages (IMs) (CD11c-expressing IMs) that are both necessary and sufficient for TSLP-mediated TH2-cell differentiation and airway inflammation. TH2-cell–driven airway eosinophilia is attenuated by ablation of CD11c-expressing IMs or by selective deficiency of TSLP receptor signaling in these cells. More importantly, CD11c-expressing IMs are sufficient for the induction of acute TH2-cell responses in the lungs that is independent of dendritic cells and T-cell priming in the draining lymph nodes. These findings indicate a novel mechanistic role for TSLP and CD11c-expressing IMs in the development of acute TH2-cell–dependent allergic airway inflammation. This work also demonstrates a new role for TSLP in promoting type 2 responses directly in the lung.