Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Regulatory T Cells Are Dispensable for Tolerance to RBC Antigens.

ABSTRACT: Autoimmune hemolytic anemia (AIHA) occurs when pathogenic autoantibodies against red blood cell (RBC) antigens are generated. While the basic disease pathology of AIHA is well studied, the underlying mechanism(s) behind the failure in tolerance to RBC autoantigens are poorly understood. Thus, to investigate the tolerance mechanisms required for the establishment and maintenance of tolerance to RBC antigens, we developed a novel murine model. With this model, we evaluated the role of regulatory T cells (Tregs) in tolerance to RBC-specific antigens. Herein, we show that neither sustained depletion of Tregs nor immunization with RBC-specific proteins in conjunction with Treg depletion led to RBC-specific autoantibody generation. Thus, these studies demonstrate that Tregs are not required to prevent autoantibodies to RBCs and suggest that other tolerance mechanisms are likely involved.

SUBMITTER: Richards AL

PROVIDER: S-EPMC5027202 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Regulatory T Cells Are Dispensable for Tolerance to RBC Antigens.

Richards Amanda L AL Kapp Linda M LM Wang Xiaohong X Howie Heather L HL Hudson Krystalyn E KE

Frontiers in immunology 20160919

Autoimmune hemolytic anemia (AIHA) occurs when pathogenic autoantibodies against red blood cell (RBC) antigens are generated. While the basic disease pathology of AIHA is well studied, the underlying mechanism(s) behind the failure in tolerance to RBC autoantigens are poorly understood. Thus, to investigate the tolerance mechanisms required for the establishment and maintenance of tolerance to RBC antigens, we developed a novel murine model. With this model, we evaluated the role of regulatory T ...[more]

PMID: 27698653

Similar Datasets

Memory of tolerance and induction of regulatory T cells by erythrocyte-targeted antigens.

Project description:New approaches based on induction of antigen-specific immunological tolerance are being explored for treatment of autoimmunity and prevention of immunity to protein drugs. Antigens associated with apoptotic debris are known to be processed tolerogenically in vivo. Our group is exploring an approach toward antigen-specific tolerization using erythrocyte-binding antigens, based on the premise that as the erythrocytes circulate, age and are cleared, the erythrocyte surface-bound antigen payload will be cleared tolerogenically along with the eryptotic debris. Here, we characterized the phenotypic signatures of CD8+ T cells undergoing tolerance in response to soluble and erythrocyte-targeted antigen. Signaling through programmed death-1/programmed death ligand-1 (PD-1/PD-L1), but not through cytotoxic T lymphocyte antigen 4 (CTLA4), was shown to be required for antigen-specific T cell deletion, anergy and expression of regulatory markers. Generation of CD25+FOXP3+ regulatory T cells in response to erythrocyte-targeted antigens but not soluble antigen at an equimolar dose was observed, and these cells were required for long-term maintenance of immune tolerance in both the CD4+ and CD8+ T cell compartments. Evidence of infectious tolerance was observed, in that tolerance to a one antigenic epitope was able to regulate responses to other epitopes in the same protein antigen.

| S-EPMC4625129 | biostudies-literature

Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver.

Project description:UnlabelledThe mechanisms of tolerance in the liver that limit susceptibility to food allergy and that mediate the acceptance of liver transplants, even with a complete major histocompatibility complex (MHC) mismatch, remain poorly defined. Here we report that in a model of liver-directed gene transfer, cytotoxic T lymphocyte (CTL) responses to non-self antigens are controlled by hepatic regulatory T cells (Tregs) that secrete the immunosuppressive cytokine interleukin (IL)-10 in response to the antigen. In addition, Kupffer cells (KCs), normally thought to initiate immune responses, are rendered tolerogenic in this context. The depletion of KCs results in a complete abrogation of IL-10 production by hepatic Tregs, indicating an interaction between Tregs and KCs in the induction of tolerance.ConclusionOur study suggests that hepatic Tregs together with KCs create a local suppressive microenvironment that prevents the establishment of the CTL response. These mechanisms provide pivotal insights and may prove instrumental in the tolerization toward non-self therapeutic proteins delivered to the liver.

| S-EPMC4380144 | biostudies-literature

Sialic acid-modified antigens impose tolerance via inhibition of T-cell proliferation and de novo induction of regulatory T cells.

Project description:Sialic acids are negatively charged nine-carbon carboxylated monosaccharides that often cap glycans on glycosylated proteins and lipids. Because of their strategic location at the cell surface, sialic acids contribute to interactions that are critical for immune homeostasis via interactions with sialic acid-binding Ig-type lectins (siglecs). In particular, these interactions may be of importance in cases where sialic acids may be overexpressed, such as on certain pathogens and tumors. We now demonstrate that modification of antigens with sialic acids (Sia-antigens) regulates the generation of antigen-specific regulatory T (Treg) cells via dendritic cells (DCs). Additionally, DCs that take up Sia-antigen prevent formation of effector CD4(+) and CD8(+)T cells. Importantly, the regulatory properties endowed on DCs upon Sia-antigen uptake are antigen-specific: only T cells responsive to the sialylated antigen become tolerized. In vivo, injection of Sia-antigen-loaded DCs increased de novo Treg-cell numbers and dampened effector T-cell expansion and IFN-γ production. The dual tolerogenic features that Sia-antigen imposed on DCs are Siglec-E-mediated and maintained under inflammatory conditions. Moreover, loading DCs with Sia-antigens not only inhibited the function of in vitro-established Th1 and Th17 effector T cells but also significantly dampened ex vivo myelin-reactive T cells, present in the circulation of mice with experimental autoimmune encephalomyelitis. These data indicate that sialic acid-modified antigens instruct DCs in an antigen-specific tolerogenic programming, enhancing Treg cells and reducing the generation and propagation of inflammatory T cells. Our data suggest that sialylation of antigens provides an attractive way to induce antigen-specific immune tolerance.

| S-EPMC4812702 | biostudies-other

CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion.

Project description:Deletion of self-antigen-specific T cells during thymic development provides protection from autoimmunity. However, it is unclear how efficiently this occurs for tissue-restricted self antigens, or how immune tolerance is maintained for self-antigen-specific T cells that routinely escape deletion. Here we show that endogenous CD4+ T cells with specificity for a set of tissue-restricted self antigens were not deleted at all. For pancreatic self antigen, this resulted in an absence of steady-state tolerance, while for the lung and intestine, tolerance was maintained by the enhanced presence of thymically-derived antigen-specific Foxp3+ regulatory T (Treg) cells. Unlike deletional tolerance, Treg cell-mediated tolerance was broken by successive antigen challenges. These findings reveal that for some tissue-restricted self antigens, tolerance relies entirely on nondeletional mechanisms that are less durable than T cell deletion. This might explain why autoimmunity is often tissue-specific, and it offers a rationale for cancer vaccine strategies targeting tissue-restricted tumor antigens.

| S-EPMC4654997 | biostudies-literature

IκBNS expression in B cells is dispensable for IgG responses to T cell-dependent antigens.

Project description:Mice lacking the atypical inhibitory kappa B (IκB) protein, IκBNS, a regulator of the NF-κB pathway encoded by the nfkbid gene, display impaired antibody responses to both T cell-independent (TI) and T cell-dependent (TD) antigens. To better understand the basis of these defects, we crossed mice carrying floxed nfkbid alleles with mice expressing Cre under the transcriptional control of the Cd79a gene to create mice that lacked IκBNS expression only in B cells. Analyses of these conditional knock-out mice revealed intact CD4+ and CD8+ T cell populations, including preserved frequencies of FoxP3+ regulatory T cells, which are known to be reduced in IκBNS knock-out mice. Like IκBNS knock-out mice, mice with conditional IκBNS ablation in B cells displayed defective IgM responses to TI antigens and a severe reduction in peritoneal B-1a cells. However, in contrast to mice lacking IκBNS altogether, the conditional IκBNS knock-out mice responded well to TD antigens compared to the control mice, with potent IgG responses following immunization with the viral antigen, rSFV-βGal or the widely used hapten-protein model antigen, NP-CGG. Furthermore, B cell intrinsic IκBNS expression was dispensable for germinal center (GC) formation and T follicular helper cell responses to NP-CGG immunization. The results presented here suggest that the defect in antibody responses to TD antigens observed in IκBNS knock-out mice results from a B cell extrinsic defect.

| S-EPMC9634154 | biostudies-literature

TGF-?-producing regulatory B cells induce regulatory T cells and promote transplantation tolerance.

Project description:Regulatory B (Breg) cells have been shown to play a critical role in immune homeostasis and in autoimmunity models. We have recently demonstrated that combined anti-T cell immunoglobulin domain and mucin domain-1 and anti-CD45RB antibody treatment results in tolerance to full MHC-mismatched islet allografts in mice by generating Breg cells that are necessary for tolerance. Breg cells are antigen-specific and are capable of transferring tolerance to untreated, transplanted animals. Here, we demonstrate that adoptively transferred Breg cells require the presence of regulatory T (Treg) cells to establish tolerance, and that adoptive transfer of Breg cells increases the number of Treg cells. Interaction with Breg cells in vivo induces significantly more Foxp3 expression in CD4(+) CD25(-) T cells than with naive B cells. We also show that Breg cells express the TGF-? associated latency-associated peptide and that Breg-cell mediated graft prolongation post-adoptive transfer is abrogated by neutralization of TGF-? activity. Breg cells, like Treg cells, demonstrate preferential expression of both C-C chemokine receptor 6 and CXCR3. Collectively, these findings suggest that in this model of antibody-induced transplantation tolerance, Breg cells promote graft survival by promoting Treg-cell development, possibly via TGF-? production.

| S-EPMC4048633 | biostudies-literature

Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance.

Project description:Central tolerance can be mediated by peripheral dendritic cells (DCs) that transport innocuous antigens (Ags) to the thymus for presentation to developing T cells, but the responsible DC subsets remained poorly defined. Immature plasmacytoid DCs (pDCs) express CCR9, a chemokine receptor involved in migration of T cell precursors to the thymus. We show here that CCR9 mediated efficient thymic entry of endogenous or i.v. transfused pDCs. pDCs activated by Toll-like receptor (TLR) ligands downregulated CCR9 and lost their ability to home to the thymus. Moreover, endogenous pDCs took up subcutaneously injected fluorescent Ag and, in the absence of TLR signals, transported Ag to the thymus in a CCR9-dependent fashion. Injected, Ag-loaded pDCs effectively deleted Ag-specific thymocytes, and this thymic clonal deletion required CCR9-mediated homing and was prevented by infectious signals. Thus, peripheral pDCs can contribute to immune tolerance through CCR9-dependent transport of peripheral Ags and subsequent deletion of Ag-reactive thymocytes.

| S-EPMC3315699 | biostudies-literature

Manipulation of Regulatory Dendritic Cells for Induction Transplantation Tolerance.

Project description:Current organ transplantation therapy is life-saving but accompanied by well-recognized side effects due to post-transplantation systematic immunosuppressive treatment. Dendritic cells (DCs) are central instigators and regulators of transplantation immunity and are responsible for balancing allograft rejection and tolerance. They are derived from monocyte-macrophage DC progenitors originating in the bone marrow and are classified into different subsets based on their developmental, phenotypical, and functional criteria. Functionally, DCs instigate allograft immunity by presenting donor antigens to alloreactive T cells via direct, indirect, and semidirect recognition pathways and provide essential signaling for alloreactive T cell activation via costimulatory molecules and pro-inflammatory cytokines. Regulatory DCs (DCregs) are characterized by a relatively low expression of major histocompatibility complex, costimulatory molecules, and altered cytokine production and exert their regulatory function through T cell anergy, T cell deletion, and regulatory T cell induction. In rodent transplantation studies, DCreg-based therapy, by in situ targeting or infusion of ex vivo generated DCregs, exhibits promising potential as a natural, well-tolerated, organ-specific therapeutic strategy for promoting lasting organ-specific transplantation tolerance. Recent early-phase studies of DCregs have begun to examine the safety and efficacy of DCreg-induced allograft tolerance in living-donor renal or liver transplantations. The present review summarizes the basic characteristics, function, and translation of DCregs in transplantation tolerance induction.

| S-EPMC7591396 | biostudies-literature

Batf3-dependent dendritic cells in the renal lymph node induce tolerance against circulating antigens.

Project description:Although the spleen is a major site where immune tolerance to circulating innocuous antigens occurs, the kidney also contributes. Circulating antigens smaller than albumin are constitutively filtered and concentrated in the kidney and reach the renal lymph node by lymphatic drainage, where resident dendritic cells (DCs) capture them and induce tolerance of specific cytotoxic T cells through unknown mechanisms. Here, we found that the coinhibitory cell surface receptor programmed death 1 (PD-1) on cytotoxic T cells mediates to their tolerance. Renal lymph node DCs of the CD8(+) XCR1(+) subset, which depend on the transcription factor Batf3, expressed the PD-1 cognate ligand PD-L1. Batf3-dependent DCs in the renal lymph node presented antigen that had been concentrated in the kidney and used PD-L1 to induce apoptosis of cytotoxic T cells. In contrast, T cell tolerance in the spleen was independent of PD-1, PD-L1, and Batf3. In summary, these results clarify how the kidney/renal lymph node system tolerizes the immune system against circulating innocuous antigens.

| S-EPMC3609142 | biostudies-literature

Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens.

Project description:Natural regulatory T (T reg) cells are involved in control of the immune response, including response to pathogens. Previous work has demonstrated that the repertoire of natural T reg cells may be biased toward self-antigen recognition. Whether they also recognize foreign antigens and how this recognition contributes to their function remain unknown. Our studies addressed the antigenic specificity of natural T reg cells that accumulate at sites of chronic infection with Leishmania major in mice. Our results support the idea that natural T reg cells are able to respond specifically to foreign antigens in that they strongly proliferate in response to Leishmania-infected dendritic cells, they maintain Foxp3 expression, and Leishmania-specific T reg cell lines can be generated from infected mice. Surprisingly, the majority of natural T reg cells at the infected site are Leishmania specific. Further, we showed that parasite-specific natural T reg cells are restricted to sites of infection and that their survival is strictly dependent on parasite persistence.

| S-EPMC2118233 | 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