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

Chao Gu; Katherine Upchurch; Joshua Horton; Mathew Wiest; Sandra Zurawski; Mark Millard; Robert R Kane; HyeMee Joo; Lisa A Miller; SangKon Oh

doi:10.3389/fimmu.2021.678036

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

Front Immunol. 2021 Jul 7:12:678036. doi: 10.3389/fimmu.2021.678036. eCollection 2021.

Authors

Chao Gu¹, Katherine Upchurch², Joshua Horton², Mathew Wiest^{1

2}, Sandra Zurawski³, Mark Millard⁴, Robert R Kane^{2

5}, HyeMee Joo^{1

2}, Lisa A Miller⁶, SangKon Oh^{1

2}

Affiliations

¹ Department of Immunology, Mayo Clinic, Scottsdale, AZ, United States.
² Institute of Biomedical Studies, Baylor University, Waco, TX, United States.
³ Baylor Research Institute, Dallas, TX, United States.
⁴ Department of Pulmonology, Baylor University Medical Center, Dallas, TX, United States.
⁵ Department of Chemistry and Biochemistry, Baylor University, Waco, TX, United States.
⁶ California National Primate Research Center, University of California, Davis, Davis, CA, United States.

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.

Keywords: Dectin-1; OX40L; STAT3; STAT6; TSLP; Th2 cells; allergy; dendritic cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Allergens / administration & dosage
Allergens / immunology
Animals
Antigens, Dermatophagoides / administration & dosage
Antigens, Dermatophagoides / immunology
Antigens, Plant / pharmacology
Case-Control Studies
Cytokines / pharmacology*
Dendritic Cells / immunology*
Dermatophagoides farinae / immunology
Disease Models, Animal
Female
HEK293 Cells
Humans
Hypersensitivity / blood
Hypersensitivity / immunology*
Immunity / drug effects*
Lectins, C-Type / agonists
Lectins, C-Type / metabolism*
Macaca mulatta
Male
Middle Aged
NF-kappa B p50 Subunit / metabolism*
OX40 Ligand / metabolism
Plant Proteins / pharmacology
STAT3 Transcription Factor / metabolism*
STAT6 Transcription Factor / metabolism*
Signal Transduction / drug effects*
Th2 Cells / drug effects
Th2 Cells / immunology*
Thymic Stromal Lymphopoietin
Transcription Factor RelB / metabolism*
beta-Glucans / pharmacology

Substances

Allergens
Amb a I protein, Ambrosia artemisiifolia
Antigens, Dermatophagoides
Antigens, Plant
CLEC7A protein, human
Cytokines
Lectins, C-Type
NF-kappa B p50 Subunit
OX40 Ligand
Plant Proteins
RELB protein, human
STAT3 Transcription Factor
STAT3 protein, human
STAT6 Transcription Factor
STAT6 protein, human
TNFSF4 protein, human
beta-Glucans
Transcription Factor RelB
curdlan
Thymic Stromal Lymphopoietin

Abstract

Publication types

MeSH terms

Substances

Grants and funding