Pathogenic Th17 inflammation is sustained in the lungs by conventional dendritic cells and TLR4 signaling

Publication date: Available online 14 November 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Karim H. Shalaby, Miranda R. Lyons-Cohen, Gregory S. Whitehead, Seddon Y. Thomas, Immo Prinz, Hideki Nakano, Donald N. Cook
BackgroundMechanisms that elicit mucosal Th17 cell responses have been described, yet how these cells are sustained in chronically inflamed tissues remains unclear.ObjectiveWe sought to understand whether the maintenance of lung Th17 inflammation requires environmental agents in addition to antigen, and to identify the lung antigen-presenting cell types (APCs) that sustain the self-renewal of Th17 cells.MethodsAnimals were repeatedly exposed to aspiration of ovalbumin alone, or together with environmental adjuvants, including extracts of common house dust (HDE), to test their role in maintaining lung inflammation. Alternatively, antigen-specific effector/memory Th17 cells, generated in culture using CD4⁺ T cells from Il17a fate-mapping mice, were adoptively transferred to assess their persistence in genetically modified animals lacking distinct lung APC subsets or cell-specific TLR4 signaling. Th17 cells were also co-cultured with lung APC subsets to determine which of these could revive their expansion and activation.ResultsTh17 cells and consequent neutrophilic inflammation were poorly sustained by inhaled antigen alone, but were augmented by inhalation of antigen together with HDE. This was associated with weight loss and changes in lung physiology consistent with interstitial lung disease. The effect of HDE required TLR4 signaling predominantly in lung hematopoietic cells, including CD11c⁺ cells. CD103⁺ and CD11b⁺ conventional dendritic cells (cDCs) directly interacted with Th17 cells in situ and revived the clonal expansion of Th17 cells ex vivo and in vivo, whereas lung macrophages and B cells could not.ConclusionTh17-dependent inflammation in the lungs can be sustained by persistent TLR4-mediated activation of lung cDCs.

Teaser

Th17 cell fate-mapping indicates that inhaled house dust extracts sustain clonal expansion of Th17 cells by conventional dendritic cells through a TLR4-dependent mechanism.


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