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.
Subject(s)
Cytokines/pharmacology , Dendritic Cells/immunology , Hypersensitivity/immunology , Immunity/drug effects , Lectins, C-Type/metabolism , NF-kappa B p50 Subunit/metabolism , STAT3 Transcription Factor/metabolism , STAT6 Transcription Factor/metabolism , Signal Transduction/drug effects , Th2 Cells/immunology , Transcription Factor RelB/metabolism , Adult , Allergens/administration & dosage , Allergens/immunology , Animals , Antigens, Dermatophagoides/administration & dosage , Antigens, Dermatophagoides/immunology , Antigens, Plant/pharmacology , Case-Control Studies , Dermatophagoides farinae/immunology , Disease Models, Animal , Female , HEK293 Cells , Humans , Hypersensitivity/blood , Lectins, C-Type/agonists , Macaca mulatta , Male , Middle Aged , OX40 Ligand/metabolism , Plant Proteins/pharmacology , Th2 Cells/drug effects , beta-Glucans/pharmacology , Thymic Stromal LymphopoietinABSTRACT
BACKGROUND: IL-10-producing regulatory B cells (Bregs) are widely ascribed immune regulatory functions. However, Breg subsets in human asthma have not been fully investigated. OBJECTIVE: We studied Breg subsets in adult allergic asthma patients by assessing two major parameters, frequency and IL-10 expression. We then investigated factors that affect these two parameters in patients. METHODS: Peripheral blood mononuclear cells (PBMCs) of adult allergic asthma patients (N = 26) and non-asthmatic controls (N = 28) were used to assess the frequency of five subsets of transitional B cells (TBs), three subsets of CD24high CD27+ B cells and B1 cells. In addition to clinical data, IL-10 expression by individual Breg subsets was assessed by flow cytometry. RESULTS: Asthma patients had decreases of CD5+ and CD1d+ CD5+ , but an increase of CD27+ TBs which was significant in patients with moderate asthma (60 < FEV1 < 80). Regardless of asthma severity, there was no significant alteration in the frequencies of 6 other Breg subsets tested. However, we found that oral corticosteroid (OCS) significantly affected the frequency of Bregs in Breg subset-specific manners. OCS decreased CD5+ and CD1d+ CD5+ TBs, but increased CD27+ TBs and CD10+ CD24high CD27+ cells. Furthermore, OCS decreased IL-10 expression by CD27+ TBs, all 3 CD24high CD27+ B cell subsets (CD5+ , CD10+ and CD1d+ ) and B1 cells. OCS-mediated inhibition of IL-10 expression was not observed in the other Breg subsets tested. CONCLUSION & CLINICAL RELEVANCE: Alterations in the frequency of Bregs and their ability to express IL-10 are Breg subset-specific. OCS treatment significantly affects the frequency as well as their ability to express IL-10 in Breg subset-specific manners.
