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

Front Immunol. 2018 Nov 13;9:2604. doi: 10.3389/fimmu.2018.02604. eCollection 2018.

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+ 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+ 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: ChIP-seq; RNA-seq; Th2 response; ZEB1; cDC1 dendritic cells; helminth infection; immune modulation; integrative genomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Interleukin-6
  • Toll-Like Receptor 9
  • ZEB1 protein, mouse
  • Zinc Finger E-box-Binding Homeobox 1
  • Interleukin-10
  • Interleukin-12