Dectin-1 Controls TSLP-Induced Th2 Response by Regulating STAT3, STAT6, and p50-RelB Activities in Dendritic Cells

• Published in: Frontiers in immunology Vol. 12; p. 678036
• Main Authors: Gu, Chao, Upchurch, Katherine, Horton, Joshua, Wiest, Mathew, Zurawski, Sandra, Millard, Mark, Kane, Robert R, Joo, HyeMee, Miller, Lisa A, Oh, SangKon
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 07-07-2021
• Subjects: Adult; Allergens - administration & dosage; Allergens - immunology; Animals; Antigens, Dermatophagoides - administration & dosage; Antigens, Dermatophagoides - immunology; Antigens, Plant - pharmacology; beta-Glucans - pharmacology; Case-Control Studies; Cytokines - pharmacology; Dectin-1; dendritic cells; Dendritic Cells - immunology; Dermatophagoides farinae - immunology; Disease Models, Animal; Female; HEK293 Cells; Humans; Hypersensitivity - blood; Hypersensitivity - immunology; Immunity - drug effects; Immunology; Lectins, C-Type - agonists; Lectins, C-Type - metabolism; Macaca mulatta; Male; Middle Aged; NF-kappa B p50 Subunit - metabolism; OX40 Ligand - metabolism; OX40L; Plant Proteins - pharmacology; Signal Transduction - drug effects; STAT3; STAT3 Transcription Factor - metabolism; STAT6; STAT6 Transcription Factor - metabolism; Th2 Cells - drug effects; Th2 Cells - immunology; Transcription Factor RelB - metabolism; TSLP; Dectin-1; dendritic cells; TSLP; OX40L; STAT3; allergy; STAT6; Th2 cells
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.678036

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
and house dust mite allergen (Der p 1)-specific IgE response in non-human primates
. 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.