1. Dectin-1 Controls TSLP-Induced Th2 Response by Regulating STAT3, STAT6, and p50-RelB Activities in Dendritic Cells
- Author
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Gu, Chao, Upchurch, Katherine, Horton, Joshua, Wiest, Mathew, Zurawski, Sandra, Millard, Mark, Kane, Robert R, Joo, HyeMee, Miller, Lisa A, and Oh, SangKon
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Vaccine Related ,Prevention ,Emerging Infectious Diseases ,Clinical Research ,Biodefense ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Adult ,Allergens ,Animals ,Antigens ,Dermatophagoides ,Antigens ,Plant ,Case-Control Studies ,Cytokines ,Dendritic Cells ,Dermatophagoides farinae ,Disease Models ,Animal ,Female ,HEK293 Cells ,Humans ,Hypersensitivity ,Immunity ,Lectins ,C-Type ,Macaca mulatta ,Male ,Middle Aged ,NF-kappa B p50 Subunit ,OX40 Ligand ,Plant Proteins ,STAT3 Transcription Factor ,STAT6 Transcription Factor ,Signal Transduction ,Th2 Cells ,Transcription Factor RelB ,beta-Glucans ,Thymic Stromal Lymphopoietin ,Dectin-1 ,TSLP ,OX40L ,dendritic cells ,STAT3 ,STAT6 ,Th2 cells ,allergy ,Medical Microbiology ,Biochemistry and cell biology ,Genetics - Abstract
The epithelium-associated cytokine thymic stromal lymphopoietin (TSLP) can induce OX40L and CCL17 expression by myeloid dendritic cells (mDCs), which contributes to aberrant Th2-type immune responses. Herein, we report that such TSLP-induced Th2-type immune response can be effectively controlled by Dectin-1, a C-type lectin receptor expressed by mDCs. Dectin-1 stimulation induced STAT3 activation and decreased the transcriptional activity of p50-RelB, both of which resulted in reduced OX40L expression on TSLP-activated mDCs. Dectin-1 stimulation also suppressed TSLP-induced STAT6 activation, resulting in decreased expression of the Th2 chemoattractant CCL17. We further demonstrated that Dectin-1 activation was capable of suppressing ragweed allergen (Amb a 1)-specific Th2-type T cell response in allergy patients ex vivo and house dust mite allergen (Der p 1)-specific IgE response in non-human primates in vivo. Collectively, this study provides a molecular explanation of Dectin-1-mediated suppression of Th2-type inflammatory responses and suggests Dectin-1 as a target for controlling Th2-type inflammation.
- Published
- 2021