GM-CSF-Facilitated Dendritic Cell Recruitment and Survival Govern the Intestinal Mucosal Response to a Mouse Enteric Bacterial Pathogen

Hirata, Yoshihiro; Egea, Laia; Dann, Sara M.; Eckmann, Lars; Kagnoff, Martin F.

doi:10.1016/j.chom.2010.01.006

Cited by 82 publications

(81 citation statements)

References 62 publications

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“…Murine inflammatory monocytes, the CD14 high human blood monocyte counterparts, are known to express CD62L and CCR2, allowing them to enter inflamed skin, but in line with Jackubzick et al (63) they might enter noninflamed peripheral tissues such as skin via hair follicles, as proposed by Nagao et al (65), and differentiate into macrophages, LCs, or remain as circulating monocytes according to the encountered environment. In line with this, sparse studies reported basal GM-CSF synthesis in human and murine skin or colonic mucosa, most predominantly by KCs and fibroblasts (66)(67)(68). Interestingly, Yasmin et al (40) have clearly shown that BMP-7 precedes TGF-b1 during embryonic life, between 8-10 and 9-11 wk estimated gestational age, respectively (69).…”

Section: Discussionmentioning

confidence: 62%

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Picarda

Chéneau

Humbert

et al. 2016

The Journal of Immunology

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Langerhans cells (LCs) are epithelial APCs that sense danger signals and in turn trigger specific immune responses. In steady-state, they participate in the maintenance of peripheral tolerance to self-antigens whereas under inflammation LCs efficiently trigger immune responses in secondary lymphoid organs. It has been demonstrated in mice that LC-deprived epithelia are rapidly replenished by short half-life langerin-expressing monocyte-derived LCs (MDLCs). These surrogate LCs are thought to be progressively replaced by langerinhigh LCs arising from self-renewing epithelial precursors of hematopoietic origin. How LCs arise from blood monocytes is not fully understood. Hence, we sought to characterize key factors that induce differentiation of langerinhigh-expressing monocyte-derived Langerhans-like cells. We identified GM-CSF and TGF-β1 as key cytokines to generate langerinhigh-expressing cells but only in serum-free conditions. These cells were shown to express the LC-specific TROP-2 and Axl surface markers and contained Birbeck granules. Surprisingly, E-cadherin was not spontaneously expressed by these cells but required a direct contact with keratinocytes to be stably induced. MDLCs induced stronger allogeneic T cell proliferations but released low amounts of inflammatory cytokines upon TLR stimulation compared with donor-paired monocyte-derived dendritic cells. Immature langerinhigh MDLCs were responsive to MIP-3β/CCL20 and CTAC/CCL27 chemokine stimulations. Finally, we demonstrated that those cells behaved as bona fide LCs when inserted in a three-dimensional rebuilt epithelium by becoming activated upon TLR or UV light stimulations. Collectively, these results prompt us to propose these langerinhigh MDLCs as a relevant model to address LC biology–related questions.

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Section: Discussionmentioning

confidence: 62%

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Picarda

Chéneau

Humbert

et al. 2016

The Journal of Immunology

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“…GM-CSF is produced at low levels in various tissues, including the intestine in the steady state, and is further induced during inflammation and infection. 20,21 Indeed, IEC-SN obtained from PTK6 cell monolayers contained low concentrations of GM-CSF (56 Ϯ 7.5 pg/ mL, n ϭ 3). Pretreatment of IEC-SN with neutralizing antibody against GM-CSF largely abrogated down-regulation of BST2 ( Figure 5A) and the enhanced inflammatory cytokine production in FL-DCs exposed to IEC-SN ( Figure 5B).…”

Section: Generation Of Cd11b ؉ Mhcii High Cdc-like Cells From Ccr9 ؊ mentioning

confidence: 99%

Identification of CCR9− murine plasmacytoid DC precursors with plasticity to differentiate into conventional DCs

Schlitzer

Loschko

Mair

et al. 2011

Blood

104

109

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Whereas the final differentiation of conventional dendritic cells (CDCs) from committed precursors occurs locally in secondary lymphoid or peripheral tissues, plasmacytoid dendritic cells (PDCs) are thought to fully develop in the bone marrow from common DC progenitors before migrating to the periphery. In our study, we define, for the first time, a subpopulation of CCR9 ؊ major histocompatibility complex class II low PDCs in murine bone marrow, which express E2-2 and are immediate precursors of CCR9 ؉ fully differentiated PDCs. However, CCR9 IntroductionAlthough plasmacytoid dendritic cells (PDCs) express markers of the "lymphoid" lineage, they can be derived from both common myeloid and common lymphoid progenitors. 1 Several elegant studies have convincingly shown that PDCs arise from common dendritic cell (DC) progenitors (or pro-DCs) in the bone marrow (BM), 2,3 which have the additional potential to generate precursor cells committed to conventional dendritic cell (CDC) development (pre-CDCs). 4,5 In contrast, common DC progenitors derived precursor cells committed exclusively to PDC development have not been described. Generation of PDCs is dependent on transcription factor E2-2, which drives the expression of other key transcription factors involved in PDC development and function (IRF8, Spi-B, IRF7) as well as PDC-specific markers (BST2 and Siglec H in murine PDCs, BDCA2 in human PDCs). 6 It has been reported that a population of Siglec-H-negative PDC-like cells in murine BM, which is only present in lymphocytic choriomeningitis virus-infected mice is capable of differentiating into CDCs during viral infection in a type I interferon (IFN)-dependent manner. 7,8 The potential of PDCs or committed PDC precursors to differentiate into other DC subpopulations in the absence of infection is unknown.It has been assumed from the available data that PDCs fully differentiate in the BM, circulate in the blood, and then enter lymphoid organs and peripheral tissues. CDCs, however, are generated from circulating committed precursors (pre-CDCs), which differentiate locally in lymphoid and peripheral tissues under the control of growth factors, such as Fms-like tyrosine kinase 3 ligand (Flt3L). 4,9 Thus, the development of CDC subpopulations is shaped by the local microenvironment allowing adaptation to tissue-specific functions. This has been shown recently for DCs in the intestinal lamina propria whose development from precursors is driven by local growth factors and the enteric microbial flora. [10][11][12] It is so far not clear whether PDCs in the intestine or in other peripheral tissues exclusively derive from fully differentiated circulating PDCs 13 or whether they can also differentiate locally from committed precursor cells under the influence of the specific tissue microenvironment.In this study, we identify an immediate PDC precursor in murine BM, which is characterized by expression of the transcription factor E2-2, PDC-specific markers (BST2, Siglec H), and production of type I IFN but lack of CCR9 and lo...

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“…The host defense against C. rodentium comprises sequential contributions from different immune cell populations, including a variety of type 3 ILC (ILC3) subsets, dendritic cells, and adaptive immune cells, including T and B lymphocytes (15)(16)(17)(18)(19)(20). Several studies have suggested an important role for Th17 cells during the course of C. rodentium infection (21)(22)(23).…”

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confidence: 99%

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

Backert

Koralov

Wirtz

et al. 2014

The Journal of Immunology

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The Citrobacter rodentium model mimics the pathogenesis of infectious colitis and requires sequential contributions from different immune cell populations, including innate lymphoid cells (ILCs) and CD4+ lymphocytes. In this study, we addressed the role of STAT3 activation in CD4+ cells during host defense in mice against C. rodentium. In mice with defective STAT3 in CD4+ cells (Stat3ΔCD4), the course of infection was unchanged during the innate lymphoid cell–dependent early phase, but significantly altered during the lymphocyte-dependent later phase. Stat3ΔCD4 mice exhibited intestinal epithelial barrier defects, including downregulation of antimicrobial peptides, increased systemic distribution of bacteria, and prolonged reduction in the overall burden of C. rodentium infection. Immunomonitoring of lamina propria cells revealed loss of virtually all IL-22–producing CD4+ lymphocytes, suggesting that STAT3 activation was required for IL-22 production not only in Th17 cells, but also in Th22 cells. Notably, the defective host defense against C. rodentium in Stat3∆CD4 mice could be fully restored by specific overexpression of IL-22 through a minicircle vector–based technology. Moreover, expression of a constitutive active STAT3 in CD4+ cells shaped strong intestinal epithelial barrier function in vitro and in vivo through IL-22, and it promoted protection from enteropathogenic bacteria. Thus, our work indicates a critical role of STAT3 activation in Th17 and Th22 cells for control of the IL-22–mediated host defense, and strategies expanding STAT3-activated CD4+ lymphocytes may be considered as future therapeutic options for improving intestinal barrier function in infectious colitis.

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GM-CSF-Facilitated Dendritic Cell Recruitment and Survival Govern the Intestinal Mucosal Response to a Mouse Enteric Bacterial Pathogen

Cited by 82 publications

References 62 publications

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Identification of CCR9− murine plasmacytoid DC precursors with plasticity to differentiate into conventional DCs

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

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