Transcription Factor KLF2 in Dendritic Cells Downregulates Th2 Programming via the HIF-1α/Jagged2/Notch Axis

Xiong, Ye; Lingrel, Jerry B.; Wüthrich, Marcel; Klein, Bruce S.; Vasudevan, Neelakantan T; Jain, Mukesh K.; George, Mariam M.; Deepe, George S.

doi:10.1128/mbio.00436-16

Cited by 17 publications

(13 citation statements)

References 41 publications

(54 reference statements)

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“…The significant down-regulation of klf2 and klf4 detected in both in vivo challenge and field samples, indicates a function in cell cycle arrest of these genes in AGD. KLF2 is also involved in immunity and suppression of KLF2 in dendritic cells has been reported to amplify Th2 responses 75 . In addition, KLF2 has been described to inhibit pro-inflammatory activation of monocytes in mammals 76 and in fish 77 .…”

Section: Discussionmentioning

confidence: 99%

Gene expression analysis of Atlantic salmon gills reveals mucin 5 and interleukin 4/13 as key molecules during amoebic gill disease

Marcos-López

Calduch-Giner

Mirimin

et al. 2018

Sci Rep

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Amoebic gill disease (AGD) is one of the main diseases affecting Atlantic salmon (Salmo salar L.) mariculture. Hallmarks of AGD are hyperplasia of the lamellar epithelium and increased production of gill mucus. This study investigated the expression of genes involved in mucus secretion, cell cycle regulation, immunity and oxidative stress in gills using a targeted 21-gene PCR array. Gill samples were obtained from experimental and natural Neoparamoeba perurans infections, and sampling points included progressive infection stages and post-freshwater treatment. Up-regulation of genes related to mucin secretion and cell proliferation, and down-regulation of pro-inflammatory and pro-apoptotic genes were associated with AGD severity, while partial restoration of the gill homeostasis was detected post-treatment. Mucins and Th2 cytokines accoun ted for most of the variability observed between groups highlighting their key role in AGD. Two mucins (muc5, muc18) showed differential regulation upon disease. Substantial up-regulation of the secreted muc5 was detected in clinical AGD, and the membrane bound muc18 showed an opposite pattern. Th2 cytokines, il4/13a and il4/13b2, were significantly up-regulated from 2 days post-infection onwards, and changes were lesion-specific. Despite the differences between experimental and natural infections, both yielded comparable results that underline the importance of the studied genes in the respiratory organs of fish, and during AGD progression.

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Section: Discussionmentioning

confidence: 99%

Gene expression analysis of Atlantic salmon gills reveals mucin 5 and interleukin 4/13 as key molecules during amoebic gill disease

Marcos-López

Calduch-Giner

Mirimin

et al. 2018

Sci Rep

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“…Interestingly, there are several reports showing upregulation of Th2 transcription factor GATA3 through IL-4 by activating STAT5 and STAT6 transcription factors (TFs), but few of them indicate that GATA3 expression can be independent of IL-4 as well ( 28 , 30 ). Apart from signaling molecules, it has been reported that IRF4 depleted DCs are unable to induce Th2 differentiation ( 28 , 31 , 32 ), whereas increased KLF2 in DCs negatively regulates Th2 induction ( 33 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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“…Thus, the role of Notch signaling in T cell responses is clearly unique to pathogen type and not easily predicted. Enhanced accumulation of Jagged 2-expressing DC due to KLF2 deficiency augmented the non-protective IL-4 response to H. capsulatum (54), supporting a role for Notch in shaping T cell responses to fungal infection. However, the effects of canonical Notch signaling on protective T cell responses necessary for fungal clearance are unknown.…”

Section: Introductionmentioning

confidence: 92%

T Cell–Restricted Notch Signaling Contributes to Pulmonary Th1 and Th2 Immunity during Cryptococcus neoformans Infection

Neal

Qiu

Chung

et al. 2017

The Journal of Immunology

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Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen but the cell signaling pathways that drive T cell responses regulating anti-fungal immunity are incompletely understood. Notch is a key signaling pathway regulating T cell development, and differentiation and functional responses of mature T cells in the periphery. Targeting of Notch signaling within T cells has been proposed as potential treatment for alloimmune and autoimmune disorders, but it is unknown whether disturbances to T cell immunity may render these patients vulnerable to fungal infections. To elucidate the role of Notch signaling during fungal infections, we infected mice expressing the pan-Notch inhibitor dominant negative Mastermind-like (DNMAML) within mature T cells with C. neoformans. Inhibition of T cell restricted Notch signaling increased fungal burdens in the lungs and CNS, diminished pulmonary leukocyte recruitment and simultaneously impaired Th1 and Th2 responses. Pulmonary leukocyte cultures from T cell Notch-deprived mice produced less IFN-γ, IL-5 and IL-13 than WT cells. This correlated with lower frequencies of IFN-γ, IL-5 and IL-13 producing CD4+ T cells; reduced expression of Th1 and Th2 associated transcription factors, Tbet and Gata3; and reduced production of IFN-γ by CD8+ T cells. In contrast, Th17 responses were largely unaffected by Notch signaling. The changes in T cell responses corresponded with impaired macrophage activation and reduced leukocyte accumulation, leading to diminished fungal control. These results identify Notch signaling as a previously unappreciated regulator of Th1 and Th2 immunity and an important element of antifungal defenses against cryptococcal infection and CNS dissemination.

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Transcription Factor KLF2 in Dendritic Cells Downregulates Th2 Programming via the HIF-1α/Jagged2/Notch Axis

Cited by 17 publications

References 41 publications

Gene expression analysis of Atlantic salmon gills reveals mucin 5 and interleukin 4/13 as key molecules during amoebic gill disease

Gene expression analysis of Atlantic salmon gills reveals mucin 5 and interleukin 4/13 as key molecules during amoebic gill disease

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

T Cell–Restricted Notch Signaling Contributes to Pulmonary Th1 and Th2 Immunity during Cryptococcus neoformans Infection

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