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1.
Immunity ; 54(12): 2698-2700, 2021 12 14.
Article in English | MEDLINE | ID: mdl-34910939

ABSTRACT

The gut houses one of the largest populations of glia in the nervous system, yet their essential functions remain unclear. New work by Progatzky et al. (2021) in Nature reveals that these enteric glia orchestrate an IFNγ-dependent immune response to helminth infection that promotes tissue repair.


Subject(s)
Intestine, Small , Neuroglia
2.
Curr Opin Immunol ; 68: 64-71, 2021 02.
Article in English | MEDLINE | ID: mdl-33130386

ABSTRACT

The gastrointestinal (GI) tract performs a set of vital physiological functions related to food and water consumption. To help regulate these complex physiological processes, the GI tract is innervated by extensive neural networks. The GI tract also serves as the largest immune organ aimed to protect hosts from harmful microbes and toxins ingested with food. It emerges that the enteric nervous and immune systems are highly integrated to optimize digestion while reinforcing immune protection. In this review, we will discuss key cellular players involved in the neuro-immune interactions within the GI mucosa with the focus on the recently uncovered neural pathways that regulate mucosal immunity in a context relevant to GI health and disease.


Subject(s)
Gastrointestinal Microbiome/immunology , Neuroimmunomodulation/immunology , Animals , Gastrointestinal Tract/immunology , Humans
3.
Sci Immunol ; 5(46)2020 04 10.
Article in English | MEDLINE | ID: mdl-32276965

ABSTRACT

Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2 +CX3CR1lo, Ccr7 +CX3CR1int (lymph migratory), and Cxcl13 +CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13 +CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7 +CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.


Subject(s)
CX3C Chemokine Receptor 1/immunology , Immunoglobulin A/immunology , Intestinal Mucosa/immunology , Macrophages/immunology , Tertiary Lymphoid Structures/immunology , Animals , Female , Gastrointestinal Microbiome/immunology , Inflammation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Salmonella enterica/immunology , Streptomycin
4.
Trends Immunol ; 41(5): 359-362, 2020 05.
Article in English | MEDLINE | ID: mdl-32249062

ABSTRACT

There is a major gap in our understanding of how the intestinal immune and nervous systems are integrated to regulate protective adaptations to enteric infections while maintaining tissue homeostasis. Three recent complementary reports published in Cell (2020) provide new mechanistic insights into how this enteric neuro-immune crosstalk may occur.


Subject(s)
Homeostasis , Intestinal Diseases , Intestines , Nervous System , Animals , Homeostasis/immunology , Humans , Intestinal Diseases/immunology , Intestinal Diseases/microbiology , Intestines/immunology , Nervous System/immunology
5.
J Neurosci ; 38(44): 9346-9354, 2018 10 31.
Article in English | MEDLINE | ID: mdl-30381426

ABSTRACT

The enteric nervous system (ENS) is a large, complex division of the peripheral nervous system that regulates many digestive, immune, hormonal, and metabolic functions. Recent advances have elucidated the dynamic nature of the mature ENS, as well as the complex, bidirectional interactions among enteric neurons, glia, and the many other cell types that are important for mediating gut behaviors. Here, we provide an overview of ENS development and maintenance, and focus on the latest insights gained from the use of novel model systems and live-imaging techniques. We discuss major advances in the understanding of enteric glia, and the functional interactions among enteric neurons, glia, and enteroendocrine cells, a large class of sensory epithelial cells. We conclude by highlighting recent work on muscularis macrophages, a group of immune cells that closely interact with the ENS in the gut wall, and the importance of neurological-immune system communication in digestive health and disease.


Subject(s)
Brain/metabolism , Enteric Nervous System/metabolism , Gastrointestinal Diseases/metabolism , Gastrointestinal Tract/metabolism , Animals , Brain/immunology , Brain/pathology , Enteric Nervous System/immunology , Enteric Nervous System/pathology , Gastrointestinal Diseases/immunology , Gastrointestinal Diseases/pathology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/pathology , Humans , Neurobiology
6.
Proc Natl Acad Sci U S A ; 114(18): E3709-E3718, 2017 05 02.
Article in English | MEDLINE | ID: mdl-28420791

ABSTRACT

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.


Subject(s)
Apoptosis , Enteric Nervous System/metabolism , Nestin/metabolism , Neurogenesis , Receptors, Nerve Growth Factor/metabolism , SOXE Transcription Factors/metabolism , Animals , Humans , Mice , Mice, Transgenic , Nestin/genetics , Receptors, Nerve Growth Factor/genetics , SOXE Transcription Factors/genetics
7.
Immunity ; 45(2): 238-9, 2016 08 16.
Article in English | MEDLINE | ID: mdl-27533011

ABSTRACT

Type 3 innate lymphoid cells (ILC3s) and enteric glia, an essential structural component of gut innervation, are well-known regulators of intestinal homeostasis. Ibiza et al. (2016) uncover a new link between commensal bacteria, enteric glial cells, and ILC3s that is required for intestinal homeostasis and defense.


Subject(s)
Dysbiosis/genetics , Gastrointestinal Microbiome/immunology , Immunity, Innate , Intestines/immunology , Lymphocytes/immunology , Neuroglia/immunology , Proto-Oncogene Proteins c-ret/metabolism , Animals , Gene Knockdown Techniques , Glial Cell Line-Derived Neurotrophic Factors/metabolism , Homeostasis , Humans , Interleukins/metabolism , Intestines/innervation , Mice , Neuroglia/microbiology , Proto-Oncogene Proteins c-ret/genetics , Symbiosis , Interleukin-22
8.
Curr Protoc Immunol ; 114: 14.39.1-14.39.14, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27479657

ABSTRACT

The unit presents a method for analysis of intestinal dendritic cell (DC) and macrophage subsets by flow cytometry in the single cell suspension prepared from the mouse small and large intestine (Basic Protocol). describes a strategy to enrich the hematopoietic cell fraction in the sample by Percoll gradient centrifugation, and describes preparation of single cell suspensions from specific tissue layers of the small intestine, such as the epithelium, villi mucosa, submucosa, and muscularis externa. Finally, Support Protocol explains how to purify specific intestinal DC and macrophage subsets by flow-cytometry-based cell sorting. © 2016 by John Wiley & Sons, Inc.


Subject(s)
Dendritic Cells/cytology , Intestinal Mucosa/cytology , Macrophages/cytology , Animals , Cell Separation , Cells, Cultured , Centrifugation, Density Gradient , Flow Cytometry , Mice , Single-Cell Analysis
9.
Cell ; 166(1): 88-101, 2016 Jun 30.
Article in English | MEDLINE | ID: mdl-27293190

ABSTRACT

Antibodies to DNA and chromatin drive autoimmunity in systemic lupus erythematosus (SLE). Null mutations and hypomorphic variants of the secreted deoxyribonuclease DNASE1L3 are linked to familial and sporadic SLE, respectively. We report that DNASE1L3-deficient mice rapidly develop autoantibodies to DNA and chromatin, followed by an SLE-like disease. Circulating DNASE1L3 is produced by dendritic cells and macrophages, and its levels inversely correlate with anti-DNA antibody response. DNASE1L3 is uniquely capable of digesting chromatin in microparticles released from apoptotic cells. Accordingly, DNASE1L3-deficient mice and human patients have elevated DNA levels in plasma, particularly in circulating microparticles. Murine and human autoantibody clones and serum antibodies from human SLE patients bind to DNASE1L3-sensitive chromatin on the surface of microparticles. Thus, extracellular microparticle-associated chromatin is a potential self-antigen normally digested by circulating DNASE1L3. The loss of this tolerance mechanism can contribute to SLE, and its restoration may represent a therapeutic opportunity in the disease.


Subject(s)
Autoantibodies/immunology , Cell-Derived Microparticles/chemistry , Chromatin/immunology , DNA/immunology , Endodeoxyribonucleases/genetics , Lupus Erythematosus, Systemic/immunology , Animals , Cell-Derived Microparticles/metabolism , Disease Models, Animal , Endodeoxyribonucleases/deficiency , Endodeoxyribonucleases/metabolism , Humans , Jurkat Cells , Lupus Erythematosus, Systemic/enzymology , Lupus Erythematosus, Systemic/genetics , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout
10.
Trends Immunol ; 37(7): 487-501, 2016 07.
Article in English | MEDLINE | ID: mdl-27289177

ABSTRACT

The gastrointestinal (GI) tract is the largest immune organ; in vertebrates, it is the only organ whose function is controlled by its own intrinsic enteric nervous system (ENS), but it is additionally regulated by extrinsic (sympathetic and parasympathetic) innervation. The GI nervous and immune systems are highly integrated in their common goal, which is to unite digestive functions with protection from ingested environmental threats. This review discusses the physiological relevance of enteric neuroimmune integration by summarizing the current knowledge of evolutionary and developmental pathways, cellular organization, and molecular mechanisms of neuroimmune interactions in health and disease.


Subject(s)
Gastrointestinal Tract/immunology , Immune System , Immunity, Mucosal , Nervous System , Neuroimmunomodulation , Animals , Biological Evolution , Gastrointestinal Tract/innervation , Homeostasis , Humans , Immune Tolerance
11.
J Immunol Methods ; 432: 13-23, 2016 May.
Article in English | MEDLINE | ID: mdl-26705686

ABSTRACT

Mononuclear phagocytes (MPs) are an essential component of the intestinal immune system. They are comprised of a few dendritic cell and macrophage subsets, all with the common ability to sample extracellular milieu and to discriminate between dangerous and innocuous signals. Despite the commonality, each MP subset acquires distinct developmental pathways and unique functions, likely to fulfill needs of the tissue in which they reside. Some MP subsets develop from monocytes and are distinguished by their expression of CX3C-chemokine receptor 1 (CX3CR1). This manuscript summarizes our expertise in vivo targeting of intestinal CX3CR1(+) MP subsets. The described tools might be useful for studies of CX3CR1(+) MP function in various murine experimental models, particularly under non-inflammatory conditions.


Subject(s)
Dendritic Cells/metabolism , Gene Targeting/methods , Immunity, Mucosal , Intestinal Mucosa/metabolism , Macrophages/metabolism , Receptors, Chemokine/deficiency , Animals , Antibodies, Monoclonal/pharmacology , Biomarkers/metabolism , CX3C Chemokine Receptor 1 , Cell Lineage , Dendritic Cells/drug effects , Dendritic Cells/immunology , Down-Regulation , Genotype , Hybridomas , Immunophenotyping , Integrases/genetics , Intestines/drug effects , Intestines/immunology , Macrophages/drug effects , Macrophages/immunology , Mice, Inbred C57BL , Mice, Knockout , Muramidase/genetics , Muramidase/immunology , Muramidase/metabolism , Phenotype , Promoter Regions, Genetic , Receptors, Chemokine/genetics , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
12.
Cell Rep ; 12(8): 1314-24, 2015 Aug 25.
Article in English | MEDLINE | ID: mdl-26279572

ABSTRACT

Generation of different CD4 T cell responses to commensal and pathogenic bacteria is crucial for maintaining a healthy gut environment, but the associated cellular mechanisms are poorly understood. Dendritic cells (DCs) and macrophages (Mfs) integrate microbial signals and direct adaptive immunity. Although the role of DCs in initiating T cell responses is well appreciated, how Mfs contribute to the generation of CD4 T cell responses to intestinal microbes is unclear. Th17 cells are critical for mucosal immune protection and at steady state are induced by commensal bacteria, such as segmented filamentous bacteria (SFB). Here, we examined the roles of mucosal DCs and Mfs in Th17 induction by SFB in vivo. We show that Mfs, and not conventional CD103(+) DCs, are essential for the generation of SFB-specific Th17 responses. Thus, Mfs drive mucosal T cell responses to certain commensal bacteria.


Subject(s)
Intestinal Mucosa/immunology , Macrophages/immunology , Microbiota/immunology , Th17 Cells/immunology , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , CX3C Chemokine Receptor 1 , Cells, Cultured , Dendritic Cells/immunology , Integrin alpha Chains/genetics , Integrin alpha Chains/metabolism , Intestinal Mucosa/microbiology , Mice , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism
13.
J Immunol Methods ; 421: 1-13, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25796561

ABSTRACT

Mononuclear phagocytes are essential for protecting against pathogens breaching the intestinal mucosa and maintaining the integrity of the gastrointestinal tract. The mononuclear phagocyte family of the healthy intestine is represented by a small population of hematopoietic cells including dendritic cells and macrophages. Distinct mononuclear phagocyte subsets strategically accumulate within and below the mucosal epithelium and are distributed in the submucosa and muscularis externa. Shaped by its unique microenvironment, each mononuclear phagocyte subset is developmentally and functionally unique and phenotypically distinct. Here we summarize our recent advances on identifying and purifying various intestinal mononuclear phagocyte subsets by flow cytometry in the context of their developmental properties and location within the intestinal tissue.


Subject(s)
Dendritic Cells/cytology , Flow Cytometry/methods , Intestinal Mucosa/cytology , Intestine, Small/cytology , Macrophages/cytology , Animals , Base Sequence , Basic-Leucine Zipper Transcription Factors/biosynthesis , Basic-Leucine Zipper Transcription Factors/genetics , Dendritic Cells/classification , Female , Gene Expression Profiling , Intestinal Mucosa/immunology , Intestine, Small/immunology , Macrophages/classification , Mice , Mice, Inbred C57BL , Mice, Knockout , Repressor Proteins/biosynthesis , Repressor Proteins/genetics , Sequence Analysis, DNA , fms-Like Tyrosine Kinase 3/biosynthesis , fms-Like Tyrosine Kinase 3/genetics
14.
Cell ; 158(2): 300-313, 2014 Jul 17.
Article in English | MEDLINE | ID: mdl-25036630

ABSTRACT

Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK:


Subject(s)
Gastrointestinal Motility , Gastrointestinal Tract/cytology , Gastrointestinal Tract/microbiology , Macrophages/metabolism , Animals , Bone Morphogenetic Protein 2/metabolism , Bone Morphogenetic Protein Receptors, Type II/metabolism , Gastrointestinal Tract/innervation , Gastrointestinal Tract/physiology , In Vitro Techniques , Macrophage Colony-Stimulating Factor , Mice , Neurons/metabolism , Peristalsis , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Signal Transduction
15.
Transplantation ; 98(5): 563-8, 2014 Sep 15.
Article in English | MEDLINE | ID: mdl-24717220

ABSTRACT

BACKGROUND: Langerhans cells (LCs) are self-renewing epidermal myeloid cells that can migrate and mature into dendritic cells. Recipient LCs that survive cytotoxic therapy given in preparation for allogeneic hematopoietic cell transplantation may prime donor T cells to mediate cutaneous graft-versus-host disease (GVHD). This possible association, however, has not been investigated in the setting of nonmyeloablative allografting. METHODS: We prospectively studied the kinetics of LC-chimerism after sex-mismatched allogeneic hematopoietic cell transplantation with nonmyeloablative (n=23) or myeloablative (n=25) conditioning. Combined XY-FISH and Langerin-staining was used to assess donor LC-chimerism in skin biopsies obtained on days 28, 56, and 84 after transplant. The degree of donor LC-chimerism was correlated with the development of skin GVHD. RESULTS: We observed significantly delayed donor LC-engraftment after nonmyeloablative transplantation compared with other hematopoietic compartments and compared with LC-engraftment after myeloablative conditioning. In most recipients of nonmyeloablative transplants, recipient LCs proliferated in situ, recruitment of donor-LCs was delayed by two months, and full donor LC-chimerism was only reached by day 84 after transplant. Although persistence of host LCs on day-28 after transplant was not predictive for acute or chronic skin GVHD, the recruitment of donor-derived LCs was associated with nonspecific inflammatory infiltrates (P=0.009). CONCLUSIONS: These results show that LCs can self-renew locally but are replaced by circulating precursors even after minimally toxic nonmyeloablative transplant conditioning. Cutaneous inflammation accompanies donor LC-engraftment, but differences in LC conversion-kinetics do not predict clinical or histopathological GVHD.


Subject(s)
Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/methods , Homeostasis , Langerhans Cells/physiology , Transplantation Chimera , Transplantation Conditioning/methods , Adult , Aged , Female , Graft vs Host Disease/prevention & control , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Prospective Studies , Transplantation, Homologous/methods
16.
Science ; 343(6178): 1249288, 2014 Mar 28.
Article in English | MEDLINE | ID: mdl-24625929

ABSTRACT

The intestinal microbiota and tissue-resident myeloid cells promote immune responses that maintain intestinal homeostasis in the host. However, the cellular cues that translate microbial signals into intestinal homeostasis remain unclear. Here, we show that deficient granulocyte-macrophage colony-stimulating factor (GM-CSF) production altered mononuclear phagocyte effector functions and led to reduced regulatory T cell (T(reg)) numbers and impaired oral tolerance. We observed that RORγt(+) innate lymphoid cells (ILCs) are the primary source of GM-CSF in the gut and that ILC-driven GM-CSF production was dependent on the ability of macrophages to sense microbial signals and produce interleukin-1ß. Our findings reveal that commensal microbes promote a crosstalk between innate myeloid and lymphoid cells that leads to immune homeostasis in the intestine.


Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Immune Tolerance , Intestines/immunology , Intestines/microbiology , Macrophages/immunology , Macrophages/microbiology , Microbiota/immunology , Animals , Antigens/immunology , Eating , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Homeostasis , Immunity, Innate , Interleukin-1beta/immunology , Mice , Mice, Mutant Strains , Mouth/immunology , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , T-Lymphocytes, Regulatory/immunology
18.
J Immunol ; 189(5): 2614-24, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22855714

ABSTRACT

Although peroxisome proliferator-activated receptor γ (PPARγ) has anti-inflammatory actions in macrophages, which macrophage populations express PPARγ in vivo and how it regulates tissue homeostasis in the steady state and during inflammation remains unclear. We now show that lung and spleen macrophages selectively expressed PPARγ among resting tissue macrophages. In addition, Ly-6C(hi) monocytes recruited to an inflammatory site induced PPARγ as they differentiated to macrophages. When PPARγ was absent in Ly-6C(hi)-derived inflammatory macrophages, initiation of the inflammatory response was unaffected, but full resolution of inflammation failed, leading to chronic leukocyte recruitment. Conversely, PPARγ activation favored resolution of inflammation in a macrophage PPARγ-dependent manner. In the steady state, PPARγ deficiency in red pulp macrophages did not induce overt inflammation in the spleen. By contrast, PPARγ deletion in lung macrophages induced mild pulmonary inflammation at the steady state and surprisingly precipitated mortality upon infection with Streptococcus pneumoniae. This accelerated mortality was associated with impaired bacterial clearance and inability to sustain macrophages locally. Overall, we uncovered critical roles for macrophage PPARγ in promoting resolution of inflammation and maintaining functionality in lung macrophages where it plays a pivotal role in supporting pulmonary host defense. In addition, this work identifies specific macrophage populations as potential targets for the anti-inflammatory actions of PPARγ agonists.


Subject(s)
Disease Resistance/immunology , Inflammation Mediators/physiology , Lung/immunology , Lung/pathology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/pathology , PPAR gamma/physiology , Animals , Gene Expression Regulation/immunology , Inflammation/immunology , Inflammation/microbiology , Inflammation/prevention & control , Inflammation Mediators/metabolism , Inflammation Mediators/therapeutic use , Lung/microbiology , Macrophages, Alveolar/microbiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , PPAR gamma/biosynthesis , PPAR gamma/deficiency , Streptococcus pneumoniae/immunology
19.
Immunity ; 36(6): 1031-46, 2012 Jun 29.
Article in English | MEDLINE | ID: mdl-22749353

ABSTRACT

GM-CSF (Csf-2) is a critical cytokine for the in vitro generation of dendritic cells (DCs) and is thought to control the development of inflammatory DCs and resident CD103(+) DCs in some tissues. Here we showed that in contrast to the current understanding, Csf-2 receptor acts in the steady state to promote the survival and homeostasis of nonlymphoid tissue-resident CD103(+) and CD11b(+) DCs. Absence of Csf-2 receptor on lung DCs abrogated the induction of CD8(+) T cell immunity after immunization with particulate antigens. In contrast, Csf-2 receptor was dispensable for the differentiation and innate function of inflammatory DCs during acute injuries. Instead, inflammatory DCs required Csf-1 receptor for their development. Thus, Csf-2 is important in vaccine-induced CD8(+) T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo.


Subject(s)
Cytokine Receptor Common beta Subunit/physiology , Dendritic Cells/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Inflammation/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation , Cell Lineage , Cytokine Receptor Common beta Subunit/antagonists & inhibitors , Cytokine Receptor Common beta Subunit/deficiency , Cytokine Receptor Common beta Subunit/genetics , Dendritic Cells/classification , Dendritic Cells/cytology , Encephalomyelitis, Autoimmune, Experimental/immunology , Endotoxemia/immunology , Gene Expression Profiling , Granulocyte-Macrophage Colony-Stimulating Factor/deficiency , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Homeostasis , Lipopolysaccharides/toxicity , Listeriosis/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/transplantation , Organ Specificity , Orthomyxoviridae Infections/immunology , Pneumococcal Infections/immunology , Radiation Chimera , Spleen/immunology , Tamoxifen/pharmacology
20.
Nat Immunol ; 13(9): 888-99, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22797772

ABSTRACT

Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8(+), CD103(+), CD11b(+) and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens.


Subject(s)
Cell Differentiation/immunology , Cell Lineage/immunology , Dendritic Cells/immunology , Transcription, Genetic , Cell Differentiation/genetics , Dendritic Cells/cytology , Gene Expression Profiling , Humans
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