Ablation of cDC2 development by triple mutations within the Zeb2 enhancer

Liu, Tian-Tian; Kim, Sun Kyung; Desai, Pritesh; Kim, Dohyun; Huang, Xingxing; Ferris, Stephen T.; Wu, Renee; Ou, Feiya; Egawa, Takeshi; Dyken, Steven J. Van; Diamond, Michael S.; Johnson, Peter F.; Kubo, Masato; Murphy, Theresa L.; Murphy, Theresa L.

doi:10.1038/s41586-022-04866-z

Cited by 42 publications

(23 citation statements)

References 54 publications

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“…Another possible function for ABC is antigen presentation to T cells (43, 45) especially membrane bound antigen (46). Consistent with this, Zeb2 has been shown to be critical for the development of cDC2 cells responsible for the priming of Th2 cells upon Heligmosomoides polygyrus infection (47, 48).…”

Section: Resultsmentioning

confidence: 54%

ZEB2 regulates the development of CD11c+ atypical B cells

Gao

Shen

Roco

et al. 2022

Preprint

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CD11c+ atypical B cells (ABC) are an alternative memory B cell lineage identified both in normal immune responses as well as pathogenic responses in autoimmunity. While it is clear that ABCs have a distinct transcriptional program, the factors that direct this program have not been identified. Here, we generated a human tonsil single-cell RNA-seq dataset and identified candidate transcription factors associated with the ABC population. We selected 8 of these transcription factors for further analysis based on their conserved expression in mouse ABC bulk RNA-seq datasets. Using an optimized CRSPR-Cas9 knockdown method we found that only zinc finger E-box binding homeobox 2 (Zeb2) knock-out impaired ABC formation. To assess the role of Zeb2 in ABC formation in vivo we used Zeb2fl/fl mice crossed to a CD23Cre line. Germinal center and plasma cell responses in these mice after Plasmodium sporozoite immunization were largely unaltered but we observed a specific defect in ABC formation. We further determined that ZEB2 haploinsufficient Mowat Wilson syndrome patients also have decreased circulating ABCs in the blood, supporting a role for this transcription factor in humans as well as mice. In sum, we identified Zeb2 as a key TF governing the formation of ABCs.

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Section: Resultsmentioning

confidence: 54%

ZEB2 regulates the development of CD11c+ atypical B cells

Gao

Shen

Roco

et al. 2022

Preprint

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“…2e ). In contrast, cDC2s were characterized by high expression of genes associated with inflammatory responses ( Cd44, Tyrobp, Bhlhe40, Fcer1g ) 22–25 ( Fig. 2f ).…”

Section: Resultsmentioning

confidence: 99%

Identification of dendritic cell-T cell interactions driving immune responses to food

Canesso

Castro

Nakandakari-Higa

et al. 2022

Preprint

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The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Dendritic cells (DCs) orchestrate these immune responses by presenting luminal antigens and inducing functional differentiation of CD4+ T cells into regulatory (pTreg) or pro-inflammatory (Th) subsets. However, the exact nature of the DCs inducing tolerance or inflammation to dietary antigens has been difficult to define. Using an intestine-adapted Labeling Immune Partnerships by SorTagging Intercellular Contacts (LIPSTIC) combined with single-cell transcriptomics, we characterized DCs presenting dietary antigens in the context of tolerance or infection. At steady-state, migratory cDC1 and cDC2 DCs, but not resident DCs, were found to present dietary antigen to cognate CD4+ T cells. Whereas cDC2s promoted T cell activation, only cDC1s induced their differentiation into pTregs. Infection with the helminth Strongyloides venezuelensis abrogated cDC1 presentation of dietary antigens, preventing pTreg and oral tolerance induction. In contrast, Heligmosomoides polygyrus infection only partially affected cDC1s, allowing oral tolerance to be maintained. An expanded population of cDC2s that induced type-2 immunity during both helminth infections did not present dietary antigens, demonstrating that compartmentalized presentation of luminal antigens can prevent food-specific Th2 responses during inflammatory conditions. Our data uncover novel cellular mechanisms by which tolerance to food is induced and can be disrupted during infections.

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“…Continuous and high expression of the transcription factors IRF8 and BATF3 is a prerequisite for maintaining the developmental and functional program of both human and murine cDC1 [ 106 , 117 , 118 , 119 ]. Genetic approaches have additionally elucidated the role of ID2 [ 120 ] and NFIL3 [ 121 , 122 ] in mouse cDC1 development, however, their implication in humans has yet to be determined. In terms of their phenotype, murine cDC1 can be reliably identified across tissues by the expression of XCR-1, CLEC9A, CD24 and CD205 [ 105 ].…”

Section: Dendritic Cells As Multifaceted Orchestrators Of Immune Resp...mentioning

confidence: 99%

“…In contrast to pDCs and cDC1 subtypes, the phenotype and developmental requirements of cDC2 between humans and mice seem to overlap the least. In mice, studies have identified transcription factors IRF-4, ZEB2, KLF4 and RELB as central mediators of cDC2 development [ 102 , 105 , 122 ] as well as pathways with more tissue-specific context such as NOTCH and retinoic acid signaling [ 127 ]. While human cDC2 distinctively expresses IRF-4, its role in their development is not yet elucidated.…”

Section: Dendritic Cells As Multifaceted Orchestrators Of Immune Resp...mentioning

confidence: 99%

Rebooting Regulatory T Cell and Dendritic Cell Function in Immune-Mediated Inflammatory Diseases: Biomarker and Therapy Discovery under a Multi-Omics Lens

et al. 2022

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Immune-mediated inflammatory diseases (IMIDs) are a group of autoimmune and chronic inflammatory disorders with constantly increasing prevalence in the modern world. The vast majority of IMIDs develop as a consequence of complex mechanisms dependent on genetic, epigenetic, molecular, cellular, and environmental elements, that lead to defects in immune regulatory guardians of tolerance, such as dendritic (DCs) and regulatory T (Tregs) cells. As a result of this dysfunction, immune tolerance collapses and pathogenesis emerges. Deeper understanding of such disease driving mechanisms remains a major challenge for the prevention of inflammatory disorders. The recent renaissance in high throughput technologies has enabled the increase in the amount of data collected through multiple omics layers, while additionally narrowing the resolution down to the single cell level. In light of the aforementioned, this review focuses on DCs and Tregs and discusses how multi-omics approaches can be harnessed to create robust cell-based IMID biomarkers in hope of leading to more efficient and patient-tailored therapeutic interventions.

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Ablation of cDC2 development by triple mutations within the Zeb2 enhancer

Cited by 42 publications

References 54 publications

ZEB2 regulates the development of CD11c+ atypical B cells

ZEB2 regulates the development of CD11c+ atypical B cells

Identification of dendritic cell-T cell interactions driving immune responses to food

Rebooting Regulatory T Cell and Dendritic Cell Function in Immune-Mediated Inflammatory Diseases: Biomarker and Therapy Discovery under a Multi-Omics Lens

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