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Mucosal Immunol. 2020 Feb 17. doi: 10.1038/s41385-020-0266-x. [Epub ahead of print]

Targeted deletion of the TSLP receptor reveals cellular mechanisms that promote type 2 airway inflammation.

Author information

1
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, 10021, USA.
2
Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Shinjuku, Tokyo, 160-8582, Japan.
3
Department of Immunology, National Institute of Infectious Diseases, Shinjuku, Tokyo, 162-8640, Japan.
4
Division of Cellular Immunology, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
5
Benaroya Research Institute, Immunology Research Program, Seattle, Washington, 98101, USA.
6
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, 10021, USA. dartis@med.cornell.edu.

Abstract

Thymic stromal lymphopoietin (TSLP) is a critical upstream cytokine inducing type 2 inflammation in various diseases, including asthma and atopic dermatitis. Accumulating evidence suggests that TSLP can directly stimulate a variety of immune cells, such as dendritic cells (DCs), basophils, T cells, and group 2 innate lymphoid cells (ILC2s). However, which cell types directly respond to TSLP in vivo and how TSLP initiates type 2 inflammation has remained controversial. To define the precise role of TSLP in vivo, for the first time we generated multiple cell lineage-specific TSLP receptor-deficient mice to systematically dissect the cell-intrinsic requirements for TSLP responsiveness in type 2 inflammation in the lung. In papain-induced innate immune-mediated type 2 airway inflammation, TSLP directly stimulated ILC2s, but not basophils, leading to enhanced type 2 inflammation. On the other hand, in OVA-induced adaptive immune-mediated type 2 airway inflammation, TSLP principally acted on DCs and CD4 + T cells during the sensitization phase, but not basophils or ILC2s, and facilitated the development of Th2 cell-mediated airway inflammation. Together, these findings reveal that TSLP activates distinct immune cell cascades in the context of innate and adaptive immune-mediated type 2 inflammation.

PMID:
32066836
DOI:
10.1038/s41385-020-0266-x

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