Genetic models of human and mouse dendritic cell development and function

Anderson, David A.; Dutertre, Charles–Antoine; Ginhoux, Florent; Murphy, Kenneth M.

doi:10.1038/s41577-020-00413-x

Cited by 208 publications

(226 citation statements)

References 250 publications

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“…Importantly, in the KPC GEMM, it has been previously reported that embryonal derived, pancreatic tissue resident macrophages, expand during PDAC progression, and have pro-tumorigenic properties, while a monocytic population is recruited from the bone marrow during tumorigenesis and has a role in antigen presentation [21]. In our KRC scRNAseq data we assigned myeloid population identities based on previously described cell type markers [16, 17, 22, 23] and observed the presence of a large macrophage population that was comprised of 3 macrophage subpopulations. These macrophages were rich in inflammatory molecules such as Ccl6, Il6 and the complement molecules C1qa and C1qb .…”

Section: Resultsmentioning

confidence: 99%

Loss of Rnf43 accelerates Kras-mediated neoplasia and remodels the tumor immune microenvironment in pancreatic adenocarcinoma

Hosein

Dangol

Okumura

et al. 2021

Preprint

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RNF43 is an E3 ubiquitin ligase that is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC) and precursor cystic neoplasms of the pancreas. The impact of RNF43 mutations on PDAC is poorly understood and autochthonous models have not been sufficiently characterized. In this study we describe a genetically engineered mouse model (GEMM) of PDAC with conditional expression of oncogenic Kras and deletion of the catalytic domain of Rnf43 (KRC) in exocrine cells. We demonstrate that Rnf43 loss results in an increased incidence of high-grade cystic lesions of the pancreas and PDAC. Importantly, KRC mice have a significantly decreased survival compared to mice containing only an oncogenic Kras mutation. By use of single cell RNA sequencing we demonstrated that KRC tumor progression is accompanied by a decrease in macrophages, as well as an increase in T and B lymphocytes with evidence of increased immune checkpoint molecule expression and affinity maturation, respectively. This was in stark contrast to the tumor immune microenvironment observed in the Kras/Tp53 driven PDAC GEMM. Furthermore, expression of the chemokine, CXCL5, was found to be specifically decreased in KRC cancer cells by means of epigenetic regulation and emerged as a putative candidate for mediating the unique KRC immune landscape. This GEMM establishes RNF43 as a bona fide tumor suppressor gene in PDAC and puts forth a rationale for an immunotherapy approach in this subset of PDAC cases.

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Section: Resultsmentioning

confidence: 99%

Loss of Rnf43 accelerates Kras-mediated neoplasia and remodels the tumor immune microenvironment in pancreatic adenocarcinoma

Hosein

Dangol

Okumura

et al. 2021

Preprint

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“…DCs in peripheral organs exist in many different subsets, which may vary between tissues [95][96][97]. In skin, Langerhans cells (LCs) represent the sole DC subset populating the epidermis, whereas the dermis hosts so-called conventional DCs (cDC1 and cDC2) as well as monocyte-derived DCs (moDCs) and plasmacytoid DCs, which get recruited into the skin inflammation.…”

Section: Dendritic Cell Migration Through Afferent Lymphatics 61 DC Types and Functional Relevance Of Migrationmentioning

confidence: 99%

“…In skin, Langerhans cells (LCs) represent the sole DC subset populating the epidermis, whereas the dermis hosts so-called conventional DCs (cDC1 and cDC2) as well as monocyte-derived DCs (moDCs) and plasmacytoid DCs, which get recruited into the skin inflammation. These DC subsets originate from different precursors and can be distinguished by the expression of different markers [95][96][97]. Furthermore, different DC subsets play distinct roles in the immune response and, for example, vary in their ability to crosspresent antigen, or to mediate immunostimulation or immunotolerance [95][96][97].…”

Section: Dendritic Cell Migration Through Afferent Lymphatics 61 DC Types and Functional Relevance Of Migrationmentioning

confidence: 99%

“…These DC subsets originate from different precursors and can be distinguished by the expression of different markers [95][96][97]. Furthermore, different DC subsets play distinct roles in the immune response and, for example, vary in their ability to crosspresent antigen, or to mediate immunostimulation or immunotolerance [95][96][97]. Besides DCs that reside in peripheral tissues and migrate via afferent lymphatics to dLNs, also resident DCs exist in SLOs.…”

Section: Dendritic Cell Migration Through Afferent Lymphatics 61 DC Types and Functional Relevance Of Migrationmentioning

confidence: 99%

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Structure and Immune Function of Afferent Lymphatics and Their Mechanistic Contribution to Dendritic Cell and T Cell Trafficking

Arasa

Collado-Díaz

Halin

2021

Cells

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Afferent lymphatic vessels (LVs) mediate the transport of antigen and leukocytes to draining lymph nodes (dLNs), thereby serving as immunologic communication highways between peripheral tissues and LNs. The main cell types migrating via this route are antigen-presenting dendritic cells (DCs) and antigen-experienced T cells. While DC migration is important for maintenance of tolerance and for induction of protective immunity, T cell migration through afferent LVs contributes to immune surveillance. In recent years, great progress has been made in elucidating the mechanisms of lymphatic migration. Specifically, time-lapse imaging has revealed that, upon entry into capillaries, both DCs and T cells are not simply flushed away with the lymph flow, but actively crawl and patrol and even interact with each other in this compartment. Detachment and passive transport to the dLN only takes place once the cells have reached the downstream, contracting collecting vessel segments. In this review, we describe how the anatomy of the lymphatic network supports leukocyte trafficking and provide updated knowledge regarding the cellular and molecular mechanisms responsible for lymphatic migration of DCs and T cells. In addition, we discuss the relevance of DC and T cell migration through afferent LVs and its presumed implications on immunity.

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“…Conventional DCs (cDCs) have been divided in two subtypes, cDC1 and cDC2, originating from a common precursor (pre-DCs) ( 8 )( 9 )( 10 )( 11 ).…”

Section: Main Textmentioning

confidence: 99%

Maturation signatures of conventional dendritic cell subtypes in COVID-19 reflect direct viral sensing

Marongiu

Protti

et al. 2021

Preprint

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Growing evidence suggests that conventional dendritic cells (cDCs) undergo aberrant maturation in COVID-19, and this adversely affects T cell activation. Here, we find that cDC2 subtypes show similar infection-induced gene signatures with an increasing gradient of expression of interferon-stimulated genes from mild to severe patients and a down-regulation of major histocompatibility complex class II (MHC class II) molecules and some inflammatory cytokines compared to the baseline level of healthy donors. In vitro, the direct exposure of cDC2s to the virus recapitulates the type of activation observed in vivo. Our findings provide evidence that SARS-CoV-2 can directly interact with cDC2s and, by down-regulating crucial molecules required for T cell activation, implements an efficient immune escape mechanism.

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Genetic models of human and mouse dendritic cell development and function

Cited by 208 publications

References 250 publications

Loss of Rnf43 accelerates Kras-mediated neoplasia and remodels the tumor immune microenvironment in pancreatic adenocarcinoma

Loss of Rnf43 accelerates Kras-mediated neoplasia and remodels the tumor immune microenvironment in pancreatic adenocarcinoma

Structure and Immune Function of Afferent Lymphatics and Their Mechanistic Contribution to Dendritic Cell and T Cell Trafficking

Maturation signatures of conventional dendritic cell subtypes in COVID-19 reflect direct viral sensing

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