Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Splenic Dendritic Cells Survey Red Blood Cells for Missing Self-CD47 to Trigger Adaptive Immune Responses.

ABSTRACT: Sheep red blood cells (SRBCs) have long been used as a model antigen for eliciting systemic immune responses, yet the basis for their adjuvant activity has been unknown. Here, we show that SRBCs failed to engage the inhibitory mouse SIRP? receptor on splenic CD4(+) dendritic cells (DCs), and this failure led to DC activation. Removal of the SIRP? ligand, CD47, from self-RBCs was sufficient to convert them into an adjuvant for adaptive immune responses. DC capture of Cd47(-/-) RBCs and DC activation occurred within minutes in a Src-family-kinase- and CD18-integrin-dependent manner. These findings provide an explanation for the adjuvant mechanism of SRBCs and reveal that splenic DCs survey blood cells for missing self-CD47, a process that might contribute to detecting and mounting immune responses against pathogen-infected RBCs.

SUBMITTER: Yi T

PROVIDER: S-EPMC4618158 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Splenic Dendritic Cells Survey Red Blood Cells for Missing Self-CD47 to Trigger Adaptive Immune Responses.

Yi Tangsheng T Li Jianhua J Chen Hsin H Wu Jiaxi J An Jinping J Xu Ying Y Hu Yongmei Y Lowell Clifford A CA Cyster Jason G JG

Immunity 20151006 4

Sheep red blood cells (SRBCs) have long been used as a model antigen for eliciting systemic immune responses, yet the basis for their adjuvant activity has been unknown. Here, we show that SRBCs failed to engage the inhibitory mouse SIRPα receptor on splenic CD4(+) dendritic cells (DCs), and this failure led to DC activation. Removal of the SIRPα ligand, CD47, from self-RBCs was sufficient to convert them into an adjuvant for adaptive immune responses. DC capture of Cd47(-/-) RBCs and DC activat ...[more]

PMID: 26453377

Similar Datasets

Splenic bridging channel dendritic cells survey red blood cells for missing self-CD47

Project description:In vivo exposure of mouse CD4+ splenic DCs to sheep red blood cells causes prompt induction of multiple genes associated with DC activation.

2015-10-01 | GSE71165 | GEO

Critical role of integrin CD11c in splenic dendritic cell capture of missing-self CD47 cells to induce adaptive immunity.

Project description: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.

| S-EPMC6042080 | biostudies-literature

Expression of the self-marker CD47 on dendritic cells governs their trafficking to secondary lymphoid organs.

Project description:Dendritic cells (DCs) capture and process Ag in the periphery. Thus, traffic through lymphatic vessels is mandatory before DCs relocate to lymph nodes where they are dedicated to T-cell priming. Here, we show that the ubiquitous self-marker CD47 selectively regulates DC, but not T and B cell trafficking across lymphatic vessels and endothelial barriers in vivo. We find an altered skin DC migration and impaired T-cell priming in CD47-deficient mice at steady state and under inflammatory conditions. Competitive DC migration assays and active immunization with myeloid DCs demonstrate that CD47 expression is required on DCs but not on the endothelium for efficient DC trafficking and T-cell responses. This migratory defect correlates with the quasi-disappearance of splenic marginal zone DCs in nonmanipulated CD47-deficient mice. Nonetheless, CCR7 expression and CCL19-driven chemotaxis remain intact. Our data reveal that CD47 on DCs is a critical factor in controlling migration and efficient initiation of the immune response.

| S-EPMC1679770 | biostudies-literature

Immunoglobulins drive terminal maturation of splenic dendritic cells.

Project description:Nature and physiological status of antigen-presenting cells, such as dendritic cells DCs, are decisive for the immune reactions elicited. Multiple factors and cell interactions have been described that affect maturation of DCs. Here, we show that DCs arising in the absence of immunoglobulins (Ig) in vivo are impaired in cross-presentation of soluble antigen. This deficiency was due to aberrant cellular targeting of antigen to lysosomes and its rapid degradation. Function of DCs could be restored by transfer of Ig irrespective of antigen specificity and isotype. Modulation of cross-presentation by Ig was inhibited by coapplication of mannan and, thus, likely to be mediated by C-type lectin receptors. This unexpected dependency of splenic DCs on Ig to cross-present antigen provides insights into the interplay between cellular and humoral immunity and the immunomodulatory capacity of Ig.

| S-EPMC3568358 | biostudies-literature

Physiologic control of IDO competence in splenic dendritic cells.

Project description:Dendritic cells (DCs) competent to express the regulatory enzyme IDO in mice are a small but distinctive subset of DCs. Previously, we reported that a high-dose systemic CpG treatment to ligate TLR9 in vivo induced functional IDO exclusively in splenic CD19(+) DCs, which stimulated resting Foxp3-lineage regulatory T cells (Tregs) to rapidly acquire potent suppressor activity. In this paper, we show that IDO was induced in spleen and peripheral lymph nodes after CpG treatment in a dose-dependent manner. Induced IDO suppressed local T cell responses to exogenous Ags and inhibited proinflammatory cytokine expression in response to TLR9 ligation. IDO induction did not occur in T cell-deficient mice or in mice with defective B7 or programmed death (PD)-1 costimulatory pathways. Consistent with these findings, CTLA4 or PD-1/PD-ligand costimulatory blockade abrogated IDO induction and prevented Treg activation via IDO following high-dose CpG treatment. Consequently, CD4(+)CD25(+) T cells uniformly expressed IL-17 shortly after TLR9 ligation. These data support the hypothesis that constitutive interactions from activated T cells or Tregs and IDO-competent DCs via concomitant CTLA4?B7 and PD-1?PD-ligand signals maintain the default potential to regulate T cell responsiveness via IDO. Acute disruption of these nonredundant interactions abrogated regulation via IDO, providing novel perspectives on the proinflammatory effects of costimulatory blockade therapies. Moreover, interactions between IDO-competent DCs and activated T cells in lymphoid tissues may attenuate proinflammatory responses to adjuvants such as TLR ligands.

| S-EPMC3556270 | biostudies-literature

Novel mechanisms underlying the immediate and transient global tolerization of splenic dendritic cells after vaccination with a self-antigen.

Project description:Dendritic cells (DCs) are important orchestrators of the immune response, ensuring that immunity against pathogens is generated, whereas immunity against healthy tissues is prevented. Using the tumor Ag MUC1, we previously showed that i.v. immunization of MUC1 transgenic mice, but not wild-type, with a MUC1 peptide resulted in transient tolerization of all splenic DCs. These DCs did not upregulate costimulatory molecules and induced regulatory T cells rather than effector T cells. They were characterized by suppressed expression of a cohort of pancreatic enzymes not previously reported in DCs, which were upregulated in DCs presenting the same MUC1 peptide as a foreign Ag. In this article, we examined the self-antigen-tolerized DC phenotype, function, and mechanisms responsible for inducing or maintaining their tolerized state. Tolerized DCs share some characteristics with immature DCs, such as a less inflammatory cytokine/chemokine profile, deficient activation of NF-κB, and sustained expression of zDC and CCR2. However, tolerized DCs demonstrated a novel inducible expression of aldehyde dehydrogenase 1/2 and phospho-STAT3. Suppressed expression of one of the pancreatic enzymes, trypsin, in these DC impeded their ability to degrade extracellular matrix, thus affecting their motility. Suppressed metallopeptidases, reflected in low expression of carboxypeptidase B1, prevented optimal Ag-specific CD4(+) T cell proliferation suggesting their role in Ag processing. Tolerized DCs were not refractory to maturation after stimulation with a TLR3 agonist, demonstrating that this tolerized state is not terminally differentiated and that tolerized DCs can recover their ability to induce immunity to foreign Ags.

| S-EPMC3897305 | biostudies-literature

Natural killer cells trigger differentiation of monocytes into dendritic cells.

Project description:Circulating monocytes can differentiate into dendritic cells (moDCs), which are potent inducers of adaptive immune responses. Previous reports show that granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 induce monocyte differentiation into moDCs in vitro, but little is known about the physiological requirements that initiate moDC differentiation in vivo. Here we show that a unique natural killer (NK) cell subset (CD3(-)CD56(bright)) that accumulates in lymph nodes and chronically inflamed tissues triggers CD14(+) monocytes to differentiate into potent T-helper-1 (T(H)1) promoting DC. This process requires direct contact of monocytes with NK cells and is mediated by GM-CSF and CD154 derived from NK cells. It is noteworthy that synovial fluid (SF) from patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), but not osteoarthritis (OA), induces monocytes to differentiate into DC. However, this process occurs only in the presence of NK cells. We propose that NK cells play a role in the maintenance of T(H)1-mediated inflammatory diseases such as RA by providing a local milieu for monocytes to differentiate into DC.

| S-EPMC1988958 | biostudies-literature

IRF7 regulates TLR2-mediated activation of splenic CD11c(hi) dendritic cells.

Project description:Members of the Interferon Regulatory Factor (IRF) family of transcription factors play an essential role in the development and function of the immune system. Here we investigated the role of IRF7 in the functional activation of conventional CD11c(hi) splenic dendritic cells (cDCs) in vitro and in vivo. Using mice deficient in IRF7, we found that this transcription factor was dispensable for the in vivo development of cDC subsets in the spleen. However, IRF7-deficient cDCs showed enhanced activation in response to microbial stimuli, characterised by exaggerated expression of CD80, CD86 and MHCII upon TLR2 ligation in vitro. The hyper-responsiveness of Irf7(-/-) cDC to TLR ligation could not be reversed with exogenous IFNα, nor by co-culture with wild-type cDCs, suggesting an intrinsic defect due to IRF7-deficiency. Irf7(-/-) cDCs also had impaired capacity to produce IL-12p70 when stimulated ex vivo, instead producing elevated levels of IL-10 that impaired their capacity to drive Th1 responses. Finally, analysis of bone marrow microchimeric mice revealed that cDCs deficient in IRF7 were also hyper-responsive to TLR2-mediated activation in vivo. Our data suggest a previously unknown function for IRF7 as a component of the regulatory network associated with cDC activation and adds to the wide variety of situations in which these transcription factors play a role.

| S-EPMC3398003 | biostudies-literature

CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells.

Project description:Foxp3(+)CD25(+)CD4(+) regulatory T cells (Treg) mediate immunological self-tolerance and suppress immune responses. A subset of dendritic cells (DCs) in the intestine is specialized to induce Treg in a TGF-beta- and retinoic acid-dependent manner to allow for oral tolerance. In this study we compare two major DC subsets from mouse spleen. We find that CD8(+) DEC-205/CD205(+) DCs, but not the major fraction of CD8(-) DC inhibitory receptor-2 (DCIR2)(+) DCs, induce functional Foxp3(+) Treg from Foxp3(-) precursors in the presence of low doses of Ag but without added TGF-beta. CD8(+)CD205(+) DCs preferentially express TGF-beta, and the induction of Treg by these DCs in vitro is blocked by neutralizing Ab to TGF-beta. In contrast, CD8(-)DCIR2(+) DCs better induce Foxp3(+) Treg when exogenous TGF-beta is supplied. In vivo, CD8(+)CD205(+) DCs likewise preferentially induce Treg from adoptively transferred, Ag-specific DO11.10 RAG(-/-) Foxp3(-)CD4(+) T cells, whereas the CD8(-)DCIR2(+) DCs better stimulate natural Foxp3(+) Treg. These results indicate that a subset of DCs in spleen, a systemic lymphoid organ, is specialized to differentiate peripheral Foxp3(+) Treg, in part through the endogenous formation of TGF-beta. Targeting of Ag to these DCs might be useful for inducing Ag-specific Foxp3(+) Treg for treatment of autoimmune diseases, transplant rejection, and allergy.

| S-EPMC2814590 | biostudies-literature

Cancer cells under immune attack acquire CD47-mediated adaptive immune resistance independent of the myeloid CD47-SIRPα axis.

Project description:Cancer cells exploit CD47 overexpression to inhibit phagocytic elimination and neoantigen processing via the myeloid CD47-SIRPα axis and thereby indirectly evade adaptive T cell immunity. Here, we report on a hitherto unrecognized direct immunoinhibitory feature of cancer cell-expressed CD47. We uncovered that in response to IFNγ released during cognate T cell immune attack, cancer cells dynamically enhance CD47 cell surface expression, which coincides with acquiring adaptive immune resistance toward pro-apoptotic effector T cell mechanisms. Indeed, CRISPR/Cas9-mediated CD47-knockout rendered cancer cells more sensitive to cognate T cell immune attack. Subsequently, we developed a cancer-directed strategy to selectively overcome CD47-mediated adaptive immune resistance using bispecific antibody (bsAb) CD47xEGFR-IgG2s that was engineered to induce rapid and prolonged cancer cell surface displacement of CD47 by internalization. Treatment of CD47pos cancer cells with bsAb CD47xEGFR-IgG2s potently enhanced susceptibility to cognate CD8pos T cells. Targeting CD47-mediated adaptive immune resistance may open up new avenues in cancer immunotherapy.

| S-EPMC8632294 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data