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

• Published in: Mucosal immunology Vol. 13; no. 4; pp. 626 - 636
• Main Authors: Kabata, Hiroki, Flamar, Anne-Laure, Mahlakõiv, Tanel, Moriyama, Saya, Rodewald, Hans-Reimer, Ziegler, Steven F., Artis, David
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.07.2020; Nature Publishing Group US; Elsevier Limited
• Subjects: Adaptive Immunity; Allergology; Animals; Antibodies; Asthma; Atopic dermatitis; Biomarkers; Biomedical and Life Sciences; Biomedicine; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell lineage; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Models, Animal; Disease Susceptibility; Gastroenterology; Gene deletion; Gene Knockdown Techniques; Gene Targeting; Helper cells; Immunity, Innate; Immunoglobulins - genetics; Immunohistochemistry; Immunology; Inflammation; Inflammation - etiology; Inflammation - metabolism; Inflammation - pathology; Leukocytes (basophilic); Lymphocytes T; Lymphoid cells; Mice; Mice, Knockout; Papain; Receptors, Cytokine - genetics; Respiratory Mucosa - immunology; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; Respiratory tract; Respiratory tract diseases; Thymic stromal lymphopoietin; Thymus
• ISSN: 1933-0219; 1935-3456; 1935-3456
• DOI: 10.1038/s41385-020-0266-x

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.