Importance of EMT Factor ZEB1 in cDC1 "MutuDC Line" Mediated Induction of Th1 Immune Response.

Details

Ressource 1Download: fimmu-09-02604.pdf (5875.51 [Ko])
State: Public
Version: Final published version
License: Not specified
Serval ID
serval:BIB_72C00C1A0AE9
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Importance of EMT Factor ZEB1 in cDC1 "MutuDC Line" Mediated Induction of Th1 Immune Response.
Journal
Frontiers in immunology
Author(s)
Smita S., Ahad A., Ghosh A., Biswas V.K., Koga M.M., Gupta B., Acha-Orbea H., Raghav S.K.
ISSN
1664-3224 (Electronic)
ISSN-L
1664-3224
Publication state
Published
Issued date
2018
Peer-reviewed
Oui
Volume
9
Pages
2604
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
The role of Epithelial to Mesenchymal Transition (EMT) factor Zeb1 is well defined in metastasis and cancer progression but it's importance in dendritic cells (DCs) is unexplored until now. For the first time we report here that Zeb1 controls immunogenic responses of CD8α <sup>+</sup> conventional Type-I (cDC1) DCs. We found that ZEB1 expression increases significantly after TLR9 stimulation and its depletion impairs activation, co-stimulation and secretion of important cytokines like IL-6, IL-10 and IL-12 in cDC1 MutuDC line. We further confirmed our findings in primary cDC1 DCs derived from bone marrow. Co-culture of these Zeb1 knock down (KD) DCs with OT-II CD4 <sup>+</sup> T helper cells skewed their differentiation toward Th2 subtype. Moreover, adoptive transfer of activated Zeb1 KD DCs cleared intestinal worms in helminth infected mice by increasing Th2 responses in vivo. Integrative genomic analysis showed Zeb1 as an activator of immune response genes in cDC1 MutuDCs as compared to other pathway genes. In addition, differentially regulated genes in Zeb1 KD RNA-seq showed significant enrichment of Th2 activation pathways supporting our in vitro findings. Mechanistically, we showed that decreased IL-12 secreted by Zeb1 KD DCs is the plausible mechanism for increased Th2 differentiation. Collectively our data demonstrate that Zeb1 could be targeted in DCs to modulate T-cell mediated adaptive immune responses.
Keywords
Adaptive Immunity/immunology, Adoptive Transfer/methods, Animals, CD4-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/immunology, Cell Differentiation/immunology, Cells, Cultured, Coculture Techniques/methods, Dendritic Cells/immunology, Epithelial-Mesenchymal Transition/immunology, Female, HEK293 Cells, Humans, Interleukin-10/immunology, Interleukin-12/immunology, Interleukin-6/immunology, Lymphocyte Activation/immunology, Mice, Mice, Inbred C57BL, T-Lymphocytes, Helper-Inducer/immunology, Th1 Cells/immunology, Th2 Cells/immunology, Toll-Like Receptor 9/immunology, Zinc Finger E-box-Binding Homeobox 1/immunology, ChIP-seq, RNA-seq, Th2 response, ZEB1, cDC1 dendritic cells, helminth infection, immune modulation, integrative genomics
Pubmed
Web of science
Open Access
Yes
Create date
29/11/2018 11:56
Last modification date
09/10/2019 6:09
Usage data