Human TSLP and TLR3 ligands promote differentiation of Th17 cells with a central memory phenotype under Th2-polarizing conditions.
BACKGROUND" Human thymic stromal lymphopoietin (TSLP) is expressed in the human asthmatic lung and activates dendritic cells (DCs) to strongly induce proallergic T-helper type 2 (Th2) cell responses, suggesting that TSLP plays a critical role in the pathophysiology of human asthma. Th2 cells are predominantly involved in mild asthma, whereas a mixture of Th1 and Th2 cells with neutrophilic inflammation, probably induced by Th17, affects more severe asthmatic disease. Exacerbation of asthmatic inflammation is often triggered by airway-targeting RNA viral infection; virus-derived double-stranded RNA, Toll-like receptor (TLR)3 ligand, activates bronchial epithelial cells to produce pro-inflammatory mediators, including TSLP.


OBJECTIVE
Because TSLPR-expressing DCs express TLR3, we examined how the relationship between TSLP and TLR3 ligand stimulation influences DC activation.


METHODS
CD11c(+)DCs purified from adult peripheral blood were cultured in TLR ligands containing media with or without TSLP and then co-cultured with allogeneic naïve CD4(+)T cells.


RESULTS
CD11c(+) DCs responded to a combination of TSLP and TLR3 ligand, poly(I : C), to up-regulate expression of the functional TSLP receptor and TLR3. Although TSLP alone did not induce IL-23 production by DCs, poly(I : C) alone primed DCs for the production of IL-23, and a combination of TSLP and poly(I : C) primed DCs for further production of IL-23. The addition of poly(I : C) did not inhibit TSLP-activated DCs to prime naïve CD4(+) T cells to differentiate into inflammatory Th2 cells. Furthermore, DCs activated by a combination of TSLP and poly(I : C) primed more naïve CD4(+) T cells to differentiate into Th17-cytokine-producing cells with a central memory T cell phenotype compared with DCs activated by poly(I : C) alone.


CONCLUSIONS
These results suggest that through DC activation, human TSLP and TLR3 ligands promote differentiation of Th17 cells with the central memory T cell phenotype under Th2-polarizing conditions.
Tanaka
J
J
Center for Innovation in Immunoregulative Technology & Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Watanabe
N
N
Kido
M
M
Saga
K
K
Akamatsu
T
T
Nishio
A
A
Chiba
T
T
D000328:Adult; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D020381:Interleukin-17 / Q000378:metabolism*; D008024:Ligands; D010641:Phenotype; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D018418:Th2 Cells / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D020381:Interleukin-17; D008024:Ligands; D051196:Toll-Like Receptor 3; D000094632:Thymic Stromal Lymphopoietin