Migration of Dendritic Cell Subsets and their Precursors (Annual Review of Immunology Book 26)

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On the other hand, LCs, which arise from fetal progenitors 13 , 62 , have, by similar methods, been shown to have self-renewal capacity, maintaining their population independently of blood-derived precursors 60 , Recently, however, Yasmin et al. During embryonic development, hematopoiesis in mammals takes place within several discrete anatomical niches whose predominance changes rapidly according to the stage of development and includes the yolk sac YS , placenta, the aorta—gonad mesonephros AGM region, the fetal liver and the BM 70—73 Fig.

In humans, hematopoiesis is initiated in the YS blood islands around day 16—18 of EGA, lasting for 3—6 weeks of the 38—40 weeks of human gestation, and giving rise to the first primitive erythroid and myeloid progenitors. The existence of self-renewing LC and macrophage precursors remains to be verified in the human, but such cells may arise from fetal progenitors. At 9 weeks EGA, the embryo is termed the fetus and remains so until birth. Broken arrows indicate relationships that require further verification in humans.

In humans, hematopoiesis is initiated in the YS blood islands around days 16—18 of estimated gestational age EGA , lasts there for 3—6 weeks of the 38—40 weeks of human gestation, and gives rise to the first primitive erythroid and myeloid progenitors. While the YS is principally responsible for primitive erythropoiesis, the fetal liver and the BM give rise to the first definitive lymphoid and myeloid progenitor cells Human pregnancy is a complex process, depending on immunological adaptations that allow the fetus to grow and develop.

While maternal cells must promote tolerance towards fetal cells and maintain effective immunity to harmful pathogens, the fetus must also recognize maternal cells and initiate an appropriate tolerogenic response against maternal cells as well as its own self-antigens.

Indeed several recent studies have highlighted the active role played by fetal immune cells in maintaining the tolerogenic environment of the fetus. Much of the initial focus on human immune development has been on lymphocytes 15 , 82—88 and, accordingly, lymphoid differentiation in humans is now well defined 77 , Intriguingly, fetal T cells are intrinsically different from adult T cells, being biased towards differentiation into T reg cells upon stimulation. This occurs irrespective of whether autologous, maternal or allogeneic antigen-presenting cells APCs are employed 9 , suggesting that fetal T cells are genuinely pre-programmed to become T reg cells upon stimulation, regardless of the precise source of that stimulation.

It is now well established that maternal cells readily cross the placenta 91 and they have been detected in fetal lymph nodes 9 , highlighting the importance of T reg cell induction to control T cells stimulated with maternal allo-antigens. Because of this intrinsic property of fetal T cells, and their accompanying distinct gene expression profile, fetal and adult T cells are considered discrete populations, arising from different populations of HSCs and exhibiting specific life-stage-appropriate characteristics It will be important in the future to understand the role played by fetal DCs in the differentiation of fetal T cells.

Two recent studies 15 , 16 have also described the crucial role of NK cells in maintaining fetal—maternal tolerance in utero. This was further established by the finding that altered decidual NK cell populations are linked with expanded T h 17 cell populations and are associated with fetal loss Additionally, a study by Ivarsson et al. For a more detailed review of the importance of NK cells in the decidua and during the first trimester of pregnancy, we refer the reader to reference In addition to T cells and NK cells, erythrocytes can also promote tolerance in the neonate, through arginase-2 activity This study combining mouse and human data suggests that the establishment of a robust tolerogenic response in the neonate is particularly important, especially in the gut, to prevent the initiation of aberrant immunity to infiltrating commensal microbes.

From 10 weeks EGA, the fetus starts to inhale amniotic fluid 94 , the cellular content of which is largely fetal as opposed to maternal.

However, there have been suggestions that the fetus may also be exposed to a minute number of maternal cells, cytokines and even some pathogens through the amniotic fluid from this period 15 , 95 , If so, the fetus must be poised to sense and to respond to a diverse range of signals from a much earlier age than previously thought. The identification of mucosa-associated invariant T MAIT cells in the fetal small intestine, liver and lung provides further support to this idea Hence, it will be intriguing to learn what leads to the generation of these cells in the fetus and the role DCs play in the process.

More detailed studies in developing human organs reported evidence of macrophage-like cells in the early pancreatic mesenchyme at 6—12 weeks EGA 97 and in the skin by 9 weeks EGA 12 , The timing of detection of these macrophage-like cells is particularly interesting, as they arise before the onset of BM hematopoiesis which commences at Whether these early macrophages persist into adulthood in human tissues has yet to be verified. However, observations in sex-mismatched donor BM transplant patients 99 and HLA-mismatched limb transplant patients 63 , where the origin of cells could be determined due to the mismatches, showed that host macrophages in the case of BM transplant, and donor macrophages in the case of limb transplant, persisted independently of blood-derived precursors , Finally, given their early appearance in embryonic tissue and their important role in maintaining tissue homeostasis in the adult , it is tempting to speculate that fetal macrophages might also play an important role in fetal tissue development and homeostasis, though the precise nature of this role remains to be defined.

The role of LCs in the fetus has not been revealed but recent studies showing adult LCs promoting tolerance 7 have led to the suggestion that LCs will have a similar role in fetal skin, where elevated levels of the immunosuppressive cytokine IL are present Ginhoux and N. McGovern, unpublished data. Because of the abundance of DCs in the fetus and their fundamental role in orchestrating immune responses in the adult, fetal DCs must also be instrumental in ensuring the appropriate immune response to maternal antigens and self-antigens during gestation.

Although the trigger for the generation of these cells remains to be determined, it is plausible that neonatal DCs and monocytes may contribute to the generation of T h 1 cells. Altogether, from the paucity of knowledge in DC functions in utero , further studies are required to determine the functional capacity of DCs in the fetus. The mature human body possesses a number of DC subsets, each playing fundamental and specialized roles in directing the appropriate immune response, whether tolerogenic or immunogenic.

Until recently, the fetal immune system was thought to be composed of immature immune cells with intrinsic defects that lead to tolerance by default.

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However, we now know that this is not the case, and that fetal immune cells can generate both tolerogenic and immunogenic responses. Given the complexity of the fetal microenvironment, it is somehow unsurprising that the fetal immune system is as diverse as the adult system. A greater understanding of fetal immunology, in particular how DCs contribute to the decision of immunity versus tolerance within the fetus, will further aid in our understanding of spontaneous abortion and help direct future intra-uterine therapies but also could provide insights in the treatment of immune-related diseases that may develop in later life.

GM-CSF–activated signaling modules regulating DC development

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Migration of dendritic cell subsets and their precursors. - Semantic Scholar

Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Four i. After i. Since the architecture of secondary lymphoid organs, e. S11 with comparable efficiency. S12A , but could present when peptide pulsed Fig. To investigate cross-presentation of influenza virus by the migrant RDC we introduce non-infectious intact influenza virion vaccine into the lungs by the i. DC found at peripheral body sites such as mucosal surfaces or the skin are not a uniform population, but rather exist as distinct cell subsets which differ in the expression of certain cell surface markers.

While the functional significance of these DC subset differences is poorly understood, different DC subsets are believed to play distinct roles in the induction and expression of innate and adaptive immune responses [1] , [39]. At least 3 mechanisms could account for the accumulation of these DC subsets in the MLN in response to respiratory infections; 1.

Although numerous studies have examined the impact of introduction of inert antigens and infectious agents into the respiratory tract on respiratory and LN DC properties and function in the induction of adaptive immune responses [7] , [41] , [44] , [45] , [46] , the relative contribution of respiratory tract-derived and LN-resident DC in driving T cell responses to respiratory tract antigens or pathogens has been difficult to define.

Indeed, there is compelling evidence that migrant RDC may function primarily in antigen transport and delivery to LN-resident DC in the draining LN which in turn are largely responsible for induction of adaptive T cell immune responses [22] , [41] , [44] , [45]. DTx administration as well as CCR7 deficiency on the numbers and migration of these inflammatory DC to the MLN during infection suggest a minor role for these cells as APC at least in the respiratory tract during natural virus infection.

Using enzymatic treatment of the disrupted MLN, we isolated sufficient numbers of these cells from the d3 p. The aforementioned study of Belz et. Kim and T. Braciale, unpublished observation.


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This result was unexpected as this RDC subset in the lung does not express markers linked to DC specialized for cross-presentation, e. Since this DC subset appears to pick up, process and present exogenous viral antigen Fig. Braciale, Manuscript in preparation.

The steady-state development of splenic dendritic cells

Braciale, Manuscript in preparation , the reason for the elevated numbers of these migrant RDC in the MLN after virus clearance [52] remains to be determined, although they may play a role as APC in memory T cell generation [53] , [54] Kim and Braciale, Manuscript in preparation. In conclusion, we have demonstrated that several distinct subsets of RDC migrate to the LN draining the respiratory tract in response to influenza virus infection. Our results indicate that antigen presenting capacity resides predominantly, if not exclusively, with the migrant RDC and only 2 of these migrant RDC subsets i.

Caton Wistar Institute, PA. Rose University of Virginia, VA. These mice were bred and housed in a pathogen-free environment and used at 9—13 wks of age for all experiments. All animal experiments were performed in accordance with protocols approved by the University of Virginia Animal Care and Use Committee. Mice were infected either i. Inactivation of infectious influenza virus was prepared by UV-crosslinking as described previously [55].

After UV exposure of the virus suspension is complete, the samples are serially diluted fold and determined for infectivity using plaque assay in MDCK cells. The non-infectious virus is delivered i. Mice were given i. The amounts of FITC-Ova taken by lung cells in uninfected mice were assessed at 1 hr post-instillation by flow cytometry and compared to unlabeled Ova. Preparation of lung single cell suspensions after enzymatic digestion were described elsewhere [27].

Briefly, Mice were sacrificed and lungs were perfused via the right ventricle of the heart with 5 ml sterile PBS to remove the intravascular pool of cells from the lung vasculature. Afterwards, lung tissues were passed though a wire screen. Viable nucleated cells in the suspensions were counted using a hemacytometer after exclusion of dead cells using Trypan blue dye. Recipient mice were infected with influenza virus 24 hr later. Cell suspensions were blocked with 2. Granzyme B was detected directly after surface staining.

A two-tailed unpaired Student t test was used to analyze differences in mean values between groups. A Flow cytometry-based categorization of RDC subpopulations.


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B Identification of AM in the lung. D Surface marker expression on subsets of RDC.

Dendritic cells - Ira Mellman (Genentech)

Total leukocytes isolated from the MLN of uninfected column A or i.