Induction of type 2 T helper cell allergen tolerance by IL-10-differentiated regulatory dendritic cells.
In mouse models of asthma, therapeutic use of allergen-presenting IL-10-differentiated dendritic cells (DCs) can abrogate airway hyperresponsiveness, and reduce other asthma-related responses to near background. Analogous human DCs can suppress human T cell responses in vitro, but the operative mechanisms are poorly defined. We investigated the ability of IL-10-treated human DCs to induce tolerance among autologous T cells of subjects with asthma and the mechanisms by which they do this. CD14(+) monocyte-derived DCs were differentiated in the presence of IL-10 (DC10) ex vivo from 11 donors with asthma and 4 control donors, and characterized for relevant markers. They were pulsed with specific or irrelevant allergen, and cultured with autologous peripheral blood CD4(+) T cells, either alone or together with autologous immunostimulatory DCs (DC-TNF), and the impact of this treatment on the T-cell responses was assessed for each donor. The DC10 expressed reduced levels of some relevant markers (CD40, CD80, human leukocyte antigen-DR) and stimulatory cytokines (IL-6 and IL-12), but augmented levels of Ig-like transcript-22/CD85j and IL-10 relative to DC-TNF. In cocultures, they dampened DC-TNF-driven T helper (Th) type 2 cell proliferation and cytokine (IL-4, -5, and -13) secretion. They also drove the development from atopic CD4(+)CD25(lo)Foxp3(lo) cells of a population of IL-10-secreting CD25(+)Foxp3(+)LAG-3(+)CTLA-4(+) regulatory T cells (Tregs). These Tregs suppressed stimulatory DC-induced autologous Th2 cell proliferation and cytokine secretion in a contact-dependent manner. Our data indicate that IL-10-treated human DCs induce Th2 cell allergen tolerance ex vivo by driving the differentiation of Tregs.
Li
Xiuling
X
Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Canada.
Yang
Aimei
A
Huang
Hui
H
Zhang
Xiaobei
X
Town
Jennifer
J
Davis
Beth
B
Cockcroft
Don W
DW
Gordon
John R
JR
D000328:Adult; D000368:Aged; D000485:Allergens / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001483:Base Sequence; D016022:Case-Control Studies; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D055815:Young Adult
D000485:Allergens; D016207:Cytokines; D017931:DNA Primers; C508609:IL10 protein, human; D016753:Interleukin-10