Flk2+ myeloid progenitors are the main source of Langerhans cells

Mende, Ines; Karsunky, Holger; Weissman, Irving L.; Engleman, Edgar G.; Mérad, Miriam

doi:10.1182/blood-2005-05-1878

Cited by 45 publications

(28 citation statements)

References 40 publications

(54 reference statements)

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“…Subsequent studies revealed that maintenance of DC developmental options by hematopoietic progenitors is linked to Flt3 expression and to their ability to respond to Flt3L. 43,87,88 Consistent with these data, enforced flt3 expression in early progenitor cells opens access to a DC differentiation program that can be used if no competing signals occur. 64 …”

Section: Early Hematopoietic Developmentsupporting

confidence: 48%

Dendritic cell homeostasis

Mérad

Manz

2009

Blood

Self Cite

332

356

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IntroductionDendritic cells (DCs) are hematopoietic cells that belong to the antigen-presenting cell (APC) family, which also includes B cells and macrophages. Although Langerhans cells (LCs) in the skin were described in 1868, the role of DCs as APCs was not appreciated until 1973, when Steinman and Cohn first identified DCs in mouse spleen as potent stimulators of the primary immune response. 1 Shortly thereafter, several groups reported the presence of DCs in nonlymphoid tissues of rodents and humans and demonstrated early evidence that these cells contribute to heart and kidney transplantation rejection. 2 However, the low number of DCs in vivo, the paucity of markers that distinguish them from monocytes/macrophages, and the problems in purifying these cells made for slow progress. In the 1990s, the development of methods to isolate and generate DCs from blood and bone marrow (BM) led to explosive growth of the DC field. [3][4][5] Studies in the last decade have established the critical role of DCs in the maintenance of immunologic integrity and their importance in the development and potential treatment of human disease, leading in 2007 to the attribution of the Albert Lasker Award for Basic Medical Research to Dr Ralph Steinman (Rockefeller University, New York, NY) in recognition of his discovery of DCs. Heterogeneity, localization, and life cycle of DC populationsDCs are a heterogeneous population of cells that can be divided into 2 major populations: (1) nonlymphoid tissue migratory and lymphoid tissue-resident DCs and (2) plasmacytoid DCs (pDCs, also called natural interferon-producing cells). The term "classic" or "conventional" DCs (cDCs) has recently been used to oppose lymphoid organ-resident DCs to pDCs. Nonlymphoid organ DCs, on the other hand, are mainly called tissue DCs. Although the term cDC is helpful in some respect, it also might be confusing as nonlymphoid tissue DCs are also different from pDCs, and primary nonlymphoid tissue DCs can be found in lymph nodes (LNs) on migration but are not cDCs. Thus, throughout this review, the term DCs will refer to all non-pDCs whether they are present in lymphoid or nonlymphoid tissues, and location will be appropriately specified.Migratory and resident DCs have 2 main functions: the maintenance of self-tolerance and the induction of specific immune responses against invading pathogens, 1,6 whereas the main function of pDCs is to secrete paramount amounts of interferon-␣ in response to viral infections and to prime T cells against viral antigens. 7 Figure 1 and Table S1 (available on the Blood website; see the Supplemental Materials link at the top of the online article) show different DC populations, their frequencies, locations, and turnover in various lympoid and nonlymphoid tissues. DCs in nonlymphoid tissuesNonlymphoid tissue DCs can be distinguished between those present in sterile tissues, such as the pancreas and the heart, DCs present in filtering sites, such as the liver and the kidney, and DCs present at environmental interfaces as lung, gut...

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Section: Early Hematopoietic Developmentsupporting

confidence: 48%

Dendritic cell homeostasis

Mérad

Manz

2009

Blood

Self Cite

332

356

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“…Upon tissue damage, such as after intense UV irradiation, circulating precursors are required for replenishment. Although both myeloid and lymphoid progenitors (particularly fetal liver kinase 2 + cells) can yield LCs, CMPs are ~20-fold more efficient in this process than are CLPs (55). In vitro, circulating human CD14 + monocytes differentiate into LCs through a CD14 + CCR6 + langerin + dermal precursor (56).…”

Section: Monocyte Differentiation Into Langerhans Cells Dermal Dcs mentioning

confidence: 99%

Monocyte-Mediated Defense Against Microbial Pathogens

Serbina

Jia

Hohl

et al. 2008

Annu. Rev. Immunol.

959

917

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Circulating blood monocytes supply peripheral tissues with macrophage and dendritic cell (DC) precursors and, in the setting of infection, also contribute directly to immune defense against microbial pathogens. In humans and mice, monocytes are divided into two major subsets that either specifically traffic into inflamed tissues or, in the absence of overt inflammation, constitutively maintain tissue macrophage/DC populations. Inflammatory monocytes respond rapidly to microbial stimuli by secreting cytokines and antimicrobial factors, express the CCR2 chemokine receptor, and traffic to sites of microbial infection in response to monocyte chemoattractant protein (MCP)-1 (CCL2) secretion. In murine models, CCR2-mediated monocyte recruitment is essential for defense against Listeria monocytogenes, Mycobacterium tuberculosis, Toxoplasma gondii, and Cryptococcus neoformans infection, implicating inflammatory monocytes in defense against bacterial, protozoal, and fungal pathogens. Recent studies indicate that inflammatory monocyte recruitment to sites of infection is complex, involving CCR2-mediated emigration of monocytes from the bone marrow into the bloodstream, followed by trafficking into infected tissues. The in vivo mechanisms that promote chemokine secretion, monocyte differentiation and trafficking, and finally monocyte-mediated microbial killing remain active and important areas of investigation.

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“…Both epidermal and dermal DC are derived from flt3 receptor-positive progenitor cells and are increased in the skin following Flt3L treatments (41)(42)(43). Enhancement of Langerhans cell production by Flt3L is likely to be important in burn injury because Langerhans cells are replaced by flt3-positive bone marrow-derived progenitor cells during skin inflammation, whereas steady-state Langerhans cells are capable of self-renewal in the skin (43). Full-thickness injuries destroy the epidermal and dermal layers, so local control of wound infection is dependent upon cells migrating to the wound from other sources, possibly including the adjacent, intact skin.…”

Section: Figurementioning

confidence: 99%

Prophylactic Treatment with Fms-Like Tyrosine Kinase-3 Ligand after Burn Injury Enhances Global Immune Responses to Infection

Bohannon

Cui²,

Cox

et al. 2008

The Journal of Immunology

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Severely burned patients are susceptible to infections with opportunistic organisms due to altered immune responses and frequent wound contamination. Immunomodulation to enhance systemic and local responses to wound infections may be protective after burn injury. We previously demonstrated that pretreatments with fms-like tyrosine kinase-3 (Flt3) ligand (Flt3L), a dendritic cell growth factor, increase the resistance of mice to a subsequent burn injury and wound infection by a dendritic cell-dependent mechanism. This study was designed to test the hypothesis that Flt3L administration after burn injury decreases susceptibility to wound infections by enhancing global immune cell activation. Mice were treated with Flt3L after burn injury and examined for survival, wound and systemic bacterial clearance, and immune cell activation after wound inoculation with Pseudomonas aeruginosa. To gain insight into the local effects of Flt3L at the burn wound, localization of Langerhans cells was examined. Mice treated with Flt3L had significantly greater numbers of CD25-expressing T cells and CD69-expressing T and B cells, neutrophils, and macrophages after, but not before, infection. Overall leukocyte apoptosis in response to infection was decreased with Flt3L treatment. Survival and local and systemic bacterial clearance were enhanced by Flt3L. Langerhans cells appeared in the dermis of skin bordering the burn wound, and further increased in response to wound infection. Flt3L augmented the appearance of Langerhans cells in response to both injury and infection. These data suggest that dendritic cell enhancement by Flt3L treatments after burn injury protects against opportunistic infections through promotion of local and systemic immune responses to infection.

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Flk2+ myeloid progenitors are the main source of Langerhans cells

Cited by 45 publications

References 40 publications

Dendritic cell homeostasis

Dendritic cell homeostasis

Monocyte-Mediated Defense Against Microbial Pathogens

Prophylactic Treatment with Fms-Like Tyrosine Kinase-3 Ligand after Burn Injury Enhances Global Immune Responses to Infection

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