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CD11c dendritic cells infiltrate the brain after ischemic injury and share some features with microglia. Gallizioli et al. show that dendritic cells exhibit a transcriptional profile different from microglia and excel in antigen presentation. Microglia attract different DC subsets via chemokines, especially cDC1 that exert beneficial functions in cerebral ischemia.Brain CD11c cells share features with microglia and dendritic cells (DCs). Sterile inflammation increases brain CD11c cells, but their phenotype, origin, and functions remain largely unknown. We report that, after cerebral ischemia, microglia attract DCs to the inflamed brain, and astroglia produce Flt3 ligand, supporting development and expansion of CD11c cells. CD11c cells in the inflamed brain are a complex population derived from proliferating microglia and infiltrating DCs, including a major subset of OX40L conventional cDC2, and also cDC1, plasmacytoid, and monocyte-derived DCs. Despite sharing certain morphological features and markers, CD11c microglia and DCs display differential expression of pattern recognition receptors and chemokine receptors. DCs excel CD11c and CD11c microglia in the capacity to present antigen through MHCI and MHCII. Of note, cDC1s protect from brain injury after ischemia. We thus reveal aspects of the dynamics and functions of brain DCs in the regulation of inflammation and immunity.

Alterations in host metabolic state have been reported to drastically alter gut microbial communities and influence host immune responses. While much attention has been paid to how the gut microbiome affects immune cell response, the reverse is understudied: how do immune cells influence the gut microbiome and in turn, regulate host metabolic state? CD11c+ cells are well known for their critical role in bridging innate and adaptive immune responses and are resident cells of almost all tissues in the body. In the gut, CD11c+ cells are located in the lamina propria and have been shown to play a key role in maintaining gut immune homeostasis. The tuberous sclerosis 1 - mechanistic target of rapamycin complex 1 (Tsc1-mTORC1) pathway is a cell’s major nutrient-sensing pathway and functions to assess nutrient availability and determine whether energy-intensive processes, such as protein translation, should take place. Specifically, Tsc1 is a negative regulator of mTORC1 and inhibits mTOR activity under conditions of low nutrient availability. Given this knowledge, we asked whether perturbing nutrient sensing in CD11c+ cells would alter the gut microbiome to ultimately influence host systemic metabolism. We generated CD11cCre x Tsc1flox/flox mice (C57BL/6J background), where Tsc1 was specifically deleted in all CD11c expressing cells. Tsc1flox/flox (“control; CTRL”) and CD11cCre x Tsc1flox/flox (“knockout; KO”) mice were housed under thermoneutral (30°C) and sub-thermoneutral conditions (22°C), and placed on normal chow diet (NCD) or high-fat diet (HFD). Weight gain, glucose and insulin sensitivity, and food intake were monitored over time. Additionally stool was collected for 16S rRNA gene sequencing. First, we determined how nutrient sensing by immune cells regulates body weight, adiposity and insulin action. Under all housing conditions, KO mice exhibited reduced weight gain as compared to CTRL mice. This decrease in body weight was not due to growth or birth defects an

We characterized a novel population of tolerogenic myeloid dendritic cells (tmDCs) defined as CD11c+ CD11b+ CD14+ CD4+ and immunoglobulin-like transcript receptor (ILT)-4+ that are significantly more abundant in the circulation of infants and young children than in adults. TmDCs secrete the immunosuppressive lymphokine interleukin (IL)-10 when stimulated with the heavy constant region of immunoglobulins (Fc) and express high levels of the adenosine A2A receptor (A2A R), which, when activated by adenosine, inhibits the release of pro-inflammatory cytokines from most immune cells. Here we show that stimulation of the A2A R on tmDCs by regadenoson or N-ethylcarboxamidoadenosine (NECA) rapidly increases cyclic AMP accumulation and enhances IL-10 production under Fc stimulatory conditions. In co-culture experiments, tmDCs inhibit the differentiation of naïve T cells to a pro-inflammatory phenotype. In conclusion, although DCs are classically viewed as antigen presenting cells that activate T cells, we show an independent role of tmDCs in pediatric immune regulation that may be important for suppressing T cell responses to neoantigens in infants and young children.

Alterations in host metabolic state have been reported to drastically alter gut microbial communities and influence host immune responses. While much attention has been paid to how the gut microbiome affects immune cell response, the reverse is understudied: how do immune cells influence the gut microbiome and in turn, regulate host metabolic state? CD11c+ cells are well known for their critical role in bridging innate and adaptive immune responses and are resident cells of almost all tissues in the body. In the gut, CD11c+ cells are located in the lamina propria and have been shown to play a key role in maintaining gut immune homeostasis. The tuberous sclerosis 1 - mechanistic target of rapamycin complex 1 (Tsc1-mTORC1) pathway is a cell’s major nutrient-sensing pathway and functions to assess nutrient availability and determine whether energy-intensive processes, such as protein translation, should take place. Specifically, Tsc1 is a negative regulator of mTORC1 and inhibits mTOR activity under conditions of low nutrient availability. Given this knowledge, we asked whether perturbing nutrient sensing in CD11c+ cells would alter the gut microbiome to ultimately influence host systemic metabolism. We generated CD11cCre x Tsc1flox/flox mice (C57BL/6J background), where Tsc1 was specifically deleted in all CD11c expressing cells. Tsc1flox/flox (“control; CTRL”) and CD11cCre x Tsc1flox/flox (“knockout; KO”) mice were housed under thermoneutral (30°C) and sub-thermoneutral conditions (22°C), and placed on normal chow diet (NCD) or high-fat diet (HFD). Weight gain, glucose and insulin sensitivity, and food intake were monitored over time. Additionally stool was collected for 16S rRNA gene sequencing. First, we determined how nutrient sensing by immune cells regulates body weight, adiposity and insulin action. Under all housing conditions, KO mice exhibited reduced weight gain as compared to CTRL mice. This decrease in body weight was not due to growth or birth defects an

We characterized a novel population of tolerogenic myeloid dendritic cells (tmDCs) defined as CD11c+ CD11b+ CD14+ CD4+ and immunoglobulin-like transcript receptor (ILT)-4+ that are significantly more abundant in the circulation of infants and young children than in adults. TmDCs secrete the immunosuppressive lymphokine interleukin (IL)-10 when stimulated with the heavy constant region of immunoglobulins (Fc) and express high levels of the adenosine A2A receptor (A2A R), which, when activated by adenosine, inhibits the release of pro-inflammatory cytokines from most immune cells. Here we show that stimulation of the A2A R on tmDCs by regadenoson or N-ethylcarboxamidoadenosine (NECA) rapidly increases cyclic AMP accumulation and enhances IL-10 production under Fc stimulatory conditions. In co-culture experiments, tmDCs inhibit the differentiation of naïve T cells to a pro-inflammatory phenotype. In conclusion, although DCs are classically viewed as antigen presenting cells that activate T cells, we show an independent role of tmDCs in pediatric immune regulation that may be important for suppressing T cell responses to neoantigens in infants and young children.

CD11c, also known as integrin alpha X, is the most widely used defining marker for dendritic cells (DCs). CD11c can bind complement iC3b and mediate phagocytosis in vitro, for which it is also referred to as complement receptor 4. However, the functions of this prominent marker protein in DCs, especially in vivo, remain poorly defined. Here, in the process of studying DC activation and immune responses induced by cells lacking self-CD47, we found that DC capture of CD47-deficient cells and DC activation was dependent on the integrin-signaling adaptor Talin1. Specifically, CD11c and its partner Itgb2 were required for DC capture of CD47-deficient cells. CD11b was not necessary for this process but could partially compensate in the absence of CD11c. Mice with DCs lacking Talin1, Itgb2, or CD11c were defective in supporting T-cell proliferation and differentiation induced by CD47-deficient cell associated antigen. These findings establish a critical role for CD11c in DC antigen uptake and activation in vivo. They may also contribute to understanding the functional mechanism of CD47-blockade therapies.

Myeloid-derived cells such as monocytes, dendritic cells (DCs), and macrophages are at the heart of the immune effector function in an inflammatory response. But because of the lack of an efficient imaging system to trace these cells live during their migration and maturation in their native environment at sub-cellular resolution, our knowledge is limited to data available from specific time-points analyzed by flow cytometry, histology, genomics and other immunological methods. Here, we have developed a ratiometric imaging method for measuring monocyte maturation in inflamed mouse lungs in situ using real-time using 2-photon imaging and complementary methods. We visualized that while undifferentiated monocytes were predominantly found only in the vasculature, a semi-differentiated monocyte/macrophage population could enter the tissue and resembled more mature and differentiated populations by morphology and surface phenotype. As these cells entered and differentiated, they were already selectively localized near inflamed airways and their entry was associated with changes in motility and morphology. We were able to visualize these during the act of differentiation, a process that can be demonstrated in this way to be faster on a per-cell basis under inflammatory conditions. Finally, our in situ analyses demonstrated increases, in the differentiating cells, for both antigen uptake and the ability to mediate interactions with T cells. This work, while largely confirming proposed models for in situ differentiation, provides important in situ data on the coordinated site-specific recruitment and differentiation of these cells and helps elaborate the predominance of immune pathology at the airways. Our novel imaging technology to trace immunogenic cell maturation in situ will complement existing information available on in situ differentiation deduced from other immunological methods, and assist better understanding of the spatio-temporal cellular behavior during an infl

Mast cell progenitors originate from the bone marrow and migrate to the lungs via the blood. During maturation, these cells acquire granules that contain a potent array of bronchoconstrictive mediators. The number of pulmonary mast cells is augmented in asthmatic patients and in mice with allergic airway inflammation, possibly contributing to airway hyperreactivity. An increase in mast cells is likely due to an increased recruitment of committed mast cell progenitors from the blood. However, until now a committed mast cell progenitor population has not been found in adult peripheral blood. We isolated Lin- c-kithi ST2+ integrin β7hi CD16/32hi progenitors from murine blood and showed that these cells were committed to the mast cell lineage. Based on the expression of FcεRI, these cells were less mature in Th1-prone C57BL/6 mice than in Th2-prone BALB/c mice. Asthma is associated with elevated levels of IgE. Upon exposure to allergens, IgE immune complexes are formed. In a mouse model of allergic airway inflammation, we showed that intranasal administration of IgE immune complexes to antigen-sensitized mice resulted in an increased number of mast cell progenitors compared with antigen administration alone. The increase in mast cell progenitors was independent of the low-affinity IgE receptor CD23. Rather, signaling through the common FcRγ-chain was required to enhance the number of lung mast cell progenitors. Signaling through FcεRI was likely responsible for the increase. However a role for FcγRIV could not be excluded. CD11c+ cells, such as dendritic cells, are important for antigen sensitization. In a mouse model of allergic airway inflammation, these cells are also important for the development of airway hyperreactivity, eosinophilia and Th2 cytokine production in response to antigen challenge. We showed that CD11c+ cells are critical for the recruitment of lung mast cell progenitors and the subsequent increase in mast cells. These CD11c+ cells were needed for the

Mast cell progenitors originate from the bone marrow and migrate to the lungs via the blood. During maturation, these cells acquire granules that contain a potent array of bronchoconstrictive mediators. The number of pulmonary mast cells is augmented in asthmatic patients and in mice with allergic airway inflammation, possibly contributing to airway hyperreactivity. An increase in mast cells is likely due to an increased recruitment of committed mast cell progenitors from the blood. However, until now a committed mast cell progenitor population has not been found in adult peripheral blood. We isolated Lin- c-kithi ST2+ integrin β7hi CD16/32hi progenitors from murine blood and showed that these cells were committed to the mast cell lineage. Based on the expression of FcεRI, these cells were less mature in Th1-prone C57BL/6 mice than in Th2-prone BALB/c mice. Asthma is associated with elevated levels of IgE. Upon exposure to allergens, IgE immune complexes are formed. In a mouse model of allergic airway inflammation, we showed that intranasal administration of IgE immune complexes to antigen-sensitized mice resulted in an increased number of mast cell progenitors compared with antigen administration alone. The increase in mast cell progenitors was independent of the low-affinity IgE receptor CD23. Rather, signaling through the common FcRγ-chain was required to enhance the number of lung mast cell progenitors. Signaling through FcεRI was likely responsible for the increase. However a role for FcγRIV could not be excluded. CD11c+ cells, such as dendritic cells, are important for antigen sensitization. In a mouse model of allergic airway inflammation, these cells are also important for the development of airway hyperreactivity, eosinophilia and Th2 cytokine production in response to antigen challenge. We showed that CD11c+ cells are critical for the recruitment of lung mast cell progenitors and the subsequent increase in mast cells. These CD11c+ cells were needed for the

Infection with viruses carrying cross-reactive antigens is associated with break of immunological tolerance and induction of autoimmune disease. Dendritic cells play an important role in this process. However, it remains unclear why autoimmune-tolerance is broken during virus infection, but usually not during exposure to non-replicating cross-reactive antigens. Here we show that antigen derived from replicating virus but not from non-replicating sources undergoes a multiplication process in dendritic cells in spleen and lymph nodes. This enforced viral replication was dependent on Usp18 and was essential for expansion of autoreactive CD8⁺ T cells. Preventing enforced virus replication by depletion of CD11c⁺ cells, genetically deleting Usp18, or pharmacologically inhibiting of viral replication blunted the expansion of autoreactive CD8⁺ T cells and prevented autoimmune diabetes. In conclusion, Usp18-driven enforced viral replication in dendritic cells can break immunological tolerance and critically influences induction of autoimmunity.

The motheaten mouse has long served as a paradigm for complex autoimmune and inflammatory disease. Null mutations in Ptpn6, which encodes the nonreceptor protein-tyrosine phosphatase Shp1, cause the motheaten phenotype. However, Shp1 regulates multiple signaling pathways in different hematopoietic cell types, so the cellular and molecular mechanism of autoimmunity and inflammation in the motheaten mouse has remained unclear. By using floxed Ptpn6 mice, we dissected the contribution of innate immune cells to the motheaten phenotype. Ptpn6 deletion in neutrophils resulted in cutaneous inflammation, but not autoimmunity, providing an animal model of human neutrophilic dermatoses. By contrast, dendritic cell deletion caused severe autoimmunity, without inflammation. Genetic and biochemical analysis showed that inflammation was caused by enhanced neutrophil integrin signaling through Src-family and Syk kinases, whereas autoimmunity resulted from exaggerated MyD88-dependent signaling in dendritic cells. Our data demonstrate that disruption of distinct Shp1-regulated pathways in different cell types combine to cause motheaten disease.

The motheaten mouse has long served as a paradigm for complex autoimmune and inflammatory disease. Null mutations in Ptpn6, which encodes the nonreceptor protein-tyrosine phosphatase Shp1, cause the motheaten phenotype. However, Shp1 regulates multiple signaling pathways in different hematopoietic cell types, so the cellular and molecular mechanism of autoimmunity and inflammation in the motheaten mouse has remained unclear. By using floxed Ptpn6 mice, we dissected the contribution of innate immune cells to the motheaten phenotype. Ptpn6 deletion in neutrophils resulted in cutaneous inflammation, but not autoimmunity, providing an animal model of human neutrophilic dermatoses. By contrast, dendritic cell deletion caused severe autoimmunity, without inflammation. Genetic and biochemical analysis showed that inflammation was caused by enhanced neutrophil integrin signaling through Src-family and Syk kinases, whereas autoimmunity resulted from exaggerated MyD88-dependent signaling in dendritic cells. Our data demonstrate that disruption of distinct Shp1-regulated pathways in different cell types combine to cause motheaten disease.

Dendritic cells can prime naive CD4+ T cells; however, here we demonstrate that dendritic cell-mediated priming was insufficient for the development of T helper type 2 cell-dependent immunity. We identify basophils as a dominant cell population that coexpressed major histocompatibility complex class II and interleukin 4 message after helminth infection. Basophilia was promoted by thymic stromal lymphopoietin, and depletion of basophils impaired immunity to helminth infection. Basophils promoted antigen-specific CD4+ T cell proliferation and interleukin 4 production in vitro, and transfer of basophils augmented the population expansion of helminth-responsive CD4+ T cells in vivo. Collectively, our studies suggest that major histocompatibility complex class II-dependent interactions between basophils and CD4+ T cells promote T helper type 2 cytokine responses and immunity to helminth infection.

Background: Dialysis with complement-activating membranes is associated with leukopenia, which is related to an increased expression of adhesion molecules on leukocytes. Citrate chelates calcium and has been claimed to attenuate leukopenia. Methods: In this study, the effects of citrate anticoagulation on leukocyte and granulocyte counts, complement activation, and the expression of CD11b, CD11c, and CD45 on the surface of granulocytes were evaluated during hemodialysis with unmodified cellulose membranes. Standard heparin was compared to citrate in three different schedules: citrate was infused to obtain a concentration of either 7 or 10 mmol/l blood. CaCl2 was administered into the dialyzer outlet at 8.25 mmol Ca2+/h (citrate 10 mmol/l) or at 11 mmol Ca2+/h (citrate 7 and 10 mmol/l) to restitute the calcium levels in the blood returning to the patient. Results: The use of citrate at a high concentration (10 mmol/l) was associated with a blunted upregulation of CD11b, both at the inlet and at the outlet bloodline; for CD11c a reduced upregulation was observed on granulocytes harvested from the inlet bloodline. No effects of citrate were observed on leukopenia, granulocytopenia, or complement activation. A positive correlation between the decrease in systemic ionized Ca2+ concentration and the increase in CD11b and CD11c expression was found. Conclusion: Citrate/CaCl2 administration affects leukocyte adhesion molecule expression in a dose- dependent way; however, no significant effect could be demonstrated on leukopenia and complement activation. Copyright (C) 2000 S. Karger AG, Basel., SCOPUS: ar.j, info:eu-repo/semantics/published