Browse
Submit Data
Databases
API
Help

Dataset Information

22 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells.

ABSTRACT: Although mature dendritic cells (DCs) are potent initiators of adaptive immune response, immature steady-state DCs contribute to immune tolerance. In this study, we show that ex vivo splenic DCs are capable of inducing conversion of naïve CD4(+) T cells to adaptive Foxp3(+)CD4(+) regulatory T cells (aTreg) in the presence of TGF-beta. In particular, when compared with splenic CD8alpha(-) DCs, the CD8alpha(+) DC subset were superior in inducing higher frequencies of conversion. This was not attributable to the difference in basal level of costimulation, because deficiency of CD40 or CD80/86 signaling did not diminish the differential induction of Foxp3. Conversion was regulated by DC maturation status. Further insights into the molecular mechanisms of conversion were gained by analyzing the contribution of several costimulatory and coinhibitory receptors. Costimulatory signals through GITR suppressed conversion, whereas coinhibitory signaling via programmed death 1 ligand (PD-L1) but not PD-L2 was required for conversion. Ex vivo PD-L1(-/-) DCs failed to support Foxp3 induction in the presence of TGF-beta. In vivo blocking PD-L1 signaling abolished conversion in a tumor-induced aTreg conversion model. Collectively, this study highlights the cellular and molecular parameters that might be exploited to control the de novo generation of aTregs and peripheral tolerance.

SUBMITTER: Wang L

PROVIDER: S-EPMC2442817 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation

Project description:We used in vitro and in vivo models to investigate PD-L1 signaling in macrophages and the effects of PD-L1 antibody treatment on Tumor associated macrophage responses

2018-07-04 | GSE116564 | GEO

FoxP3? regulatory CD4 T cells control the generation of functional CD8 memory.

Project description:During the primary immune response, CD8 memory emerges from an environment of strong immune activation. The FoxP3(+) regulatory CD4 T-cell subset (Treg) is known as a key suppressive component of the immune system. Here we report that Tregs are required for the generation of functional CD8 memory. In the absence of Tregs during priming, the resulting memory cells proliferate poorly and fail to differentiate into functional cytotoxic secondary effectors following antigen reactivation. We find that the Tregs act early, during the expansion phase of primary CD8 effectors, by fine tuning interleukin-2 exposure of CD8 memory precursors. This crucial new role of Tregs has implications for optimal vaccine development.

| S-EPMC3432473 | biostudies-other

Programmed death ligand-1/programmed death-1 inhibition therapy and programmed death ligand-1 expression in urothelial bladder carcinoma.

Project description:After two decades of unchanged paradigms, the treatment strategies for advanced urothelial bladder cancer have been revolutionized by emerging programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) inhibition therapy. Increased evidence is demonstrating the efficacy of PD-L1/PD1 inhibition therapy in both second-line and first-line settings. However, the percentage of patients who benefit from anti-PD-L1/anti-PD1 therapy is still low. Many questions have been raised in the development of biomarker-driven approaches for disease classification and patient selection. In this perspective, we discuss PD-L1/PD1 expression in urothelial bladder carcinoma, review approved anti-PD-L1/anti-PD1 agents for bladder cancer treatment and current ongoing studies investigating combination treatment strategies, and explore PD-L1 expression status for the evaluation of bladder cancer immunotherapy.

| S-EPMC6926111 | biostudies-literature

Mycobacteria-responsive sonic hedgehog signaling mediates programmed death-ligand 1- and prostaglandin E2-induced regulatory T cell expansion.

Project description:CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) are exploited by mycobacteria to subvert the protective host immune responses. The Treg expansion in the periphery requires signaling by professional antigen presenting cells and in particularly dendritic cells (DC). However, precise molecular mechanisms by which mycobacteria instruct Treg expansion via DCs are not established. Here we demonstrate that mycobacteria-responsive sonic hedgehog (SHH) signaling in human DCs leads to programmed death ligand-1 (PD-L1) expression and cyclooxygenase (COX)-2-catalyzed prostaglandin E2 (PGE2) that orchestrate mycobacterial infection-induced expansion of Tregs. While SHH-responsive transcription factor GLI1 directly arbitrated COX-2 transcription, specific microRNAs, miR-324-5p and miR-338-5p, which target PD-L1 were downregulated by SHH signaling. Further, counter-regulatory roles of SHH and NOTCH1 signaling during mycobacterial-infection of human DCs was also evident. Together, our results establish that Mycobacterium directs a fine-balance of host signaling pathways and molecular regulators in human DCs to expand Tregs that favour immune evasion of the pathogen.

| S-EPMC4832185 | biostudies-literature

mTOR Complex 1 Signaling Regulates the Generation and Function of Central and Effector Foxp3+ Regulatory T Cells.

Project description:The mechanistic/mammalian target of rapamycin (mTOR) has emerged as a critical integrator of signals from the immune microenvironment capable of regulating T cell activation, differentiation, and function. The precise role of mTOR in the control of regulatory T cell (Treg) differentiation and function is complex. Pharmacologic inhibition and genetic deletion of mTOR promotes the generation of Tregs even under conditions that would normally promote generation of effector T cells. Alternatively, mTOR activity has been observed to be increased in Tregs, and the genetic deletion of the mTOR complex 1 (mTORC1)-scaffold protein Raptor inhibits Treg function. In this study, by employing both pharmacologic inhibitors and genetically altered T cells, we seek to clarify the role of mTOR in Tregs. Our studies demonstrate that inhibition of mTOR during T cell activation promotes the generation of long-lived central Tregs with a memory-like phenotype in mice. Metabolically, these central memory Tregs possess enhanced spare respiratory capacity, similar to CD8+ memory cells. Alternatively, the generation of effector Tregs (eTregs) requires mTOR function. Indeed, genetic deletion of Rptor leads to the decreased expression of ICOS and PD-1 on the eTregs. Overall, our studies define a subset of mTORC1hi eTregs and mTORC1lo central Tregs.

| S-EPMC6089237 | biostudies-literature

Connexin 43 signaling enhances the generation of Foxp3+ regulatory T cells.

Project description:Despite their importance for the functioning of the immune system, thymic development and peripheral maintenance of Foxp3(+) regulatory T (T(R)) cells are poorly understood. We have found that connexin 43 (Cx43), expressed by thymic T(R) cells progenitors, supports T(R) development. Mice with deletion of the Cx43 gene induced in T cells produce only few T(R) cells and had increased proportion of activated T cells in the lymph nodes, suggesting impaired peripheral tolerance. Reduction of the T(R) cell numbers was accompanied by increased presence of CD4(+)CD25(+)GITR(+)Foxp3(-) T cells, which did not produce inflammatory cytokines and lost suppressor function. These results strongly argue that we have discovered a novel signaling pathway, controlled by Cx43, that enhances the generation of T(R) cells. We propose that a possible mechanism of Cx43 activity is by regulating Foxp3 expression in T(R) lineage cells.

| S-EPMC3119766 | biostudies-literature

OX40 ligand and programmed cell death 1 ligand 2 expression on inflammatory dendritic cells regulates CD4 T cell cytokine production in the lung during viral disease.

Project description:CD4 Th differentiation is influenced by costimulatory molecules expressed on conventional dendritic cells (DCs) in regional lymph nodes and results in specific patterns of cytokine production. However, the function of costimulatory molecules on inflammatory (CD11b(+)) DCs in the lung during recall responses is not fully understood, but it is important for development of novel interventions to limit immunopathological responses to infection. Using a mouse model in which vaccination with vaccinia virus vectors expressing the respiratory syncytial virus (RSV) fusion protein (rVVF) or attachment protein (rVVG) leads to type 1- or type 2-biased cytokine responses, respectively, upon RSV challenge, we found expression of CD40 and OX40 ligand (OX40L) on lung inflammatory DCs was higher in rVVF-primed mice than in rVVG-primed mice early after RSV challenge, whereas the reverse was observed later in the response. Conversely, programmed cell death 1 ligand 2 (PD-L2) was higher in rVVG-primed mice throughout. Inflammatory DCs isolated at the resolution of inflammation revealed that OX40L on type 1-biased DCs promoted IL-5, whereas OX40L on type 2-biased DCs enhanced IFN-? production by Ag-reactive Th cells. In contrast, PD-L2 promoted IFN-? production, irrespective of conditions, suppressing IL-5 only if expressed on type 1-biased DCs. Thus, OX40L and PD-L2 expressed on DCs differentially regulate cytokine production during recall responses in the lung. Manipulation of these costimulatory pathways may provide a novel approach to controlling pulmonary inflammatory responses.

| S-EPMC3276844 | biostudies-literature

Programmed death-ligand 1 expression in swine chronic infections and enhancement of interleukin-2 production via programmed death-1/programmed death-ligand 1 blockade.

Project description:IntroductionChronic infections lead to the functional exhaustion of T cells. Exhausted T cells are phenotypically differentiated by the surface expression of the immunoinhibitory receptor, such as programmed death-1 (PD-1). The inhibitory signal is produced by the interaction between PD-1 and its PD-ligand 1 (PD-L1) and impairs the effector functions of T cells. However, the expression dynamics of PD-L1 and the immunological functions of the PD-1/PD-L1 pathway in chronic diseases of pigs are still poorly understood. In this study, we first analyzed the expression of PD-L1 in various chronic infections in pigs, and then evaluated the immune activation by the blocking assay targeting the swine PD-1/PD-L1 pathway.MethodsIn the initial experiments, anti-bovine PD-L1 monoclonal antibodies (mAbs) were tested for cross-reactivity with swine PD-L1. Subsequently, immunohistochemical analysis was conducted using the anti-PD-L1 mAb. Finally, we assessed the immune activation of swine peripheral blood mononuclear cells (PBMCs) by the blockade with anti-PD-L1 mAb.ResultsSeveral anti-PD-L1 mAbs tested recognized swine PD-L1-expressing cells. The binding of swine PD-L1 protein to swine PD-1 was inhibited by some of these cross-reactive mAbs. In addition, immunohistochemical analysis revealed that PD-L1 was expressed at the site of infection in chronic infections of pigs. The PD-L1 blockade increased the production of interleukin-2 from swine PBMCs.ConclusionsThese findings suggest that the PD-1/PD-L1 pathway could be also involved in immunosuppression in chronic infections in pigs. This study provides a new perspective on therapeutic strategies for chronic diseases in pigs by targeting immunosuppressive pathways.

| S-EPMC8589367 | biostudies-literature

Sorting nexin 6 interacts with Cullin3 and regulates programmed death ligand 1 expression.

Project description:Programmed death ligand 1 (PD-L1) is critical for the ability of cancer cells to evade attacks by the host immune system. However, the molecular mechanisms controlling PD-L1 expression have not been fully understood. Here, we demonstrate that sorting nexin 6 (SNX6) is a novel regulator of PD-L1 expression. Knockdown of SNX6 in cancer cells significantly decreases PD-L1 protein levels. In contrast, loss of SNX6 does not reduce PD-L1 mRNA levels. Instead, SNX6 interacts with Cullin3, an E3 ubiquitin ligase responsible for PD-L1 ubiquitination and subsequent degradation. By binding with Cullin3, SNX6 decreases the interaction between the adaptor protein speckle-type POZ protein and Cullin3, which in turn downregulates Cullin3-mediated PD-L1 ubiquitination. This research reveals a novel molecular nexus in modulating PD-L1.

| S-EPMC8545913 | biostudies-literature

Programmed Cell Death Ligand (PD-L)-1 Contributes to the Regulation of CD4<sup>+</sup> T Effector and Regulatory T Cells in Cutaneous Leishmaniasis.

Project description:Cutaneous Leishmaniasis (CL) affects up to one million people every year and treatments are costly and toxic. The regulation of the host immune response is complex and the knowledge of how CD4+ T cells are activated and maintained during Leishmania infection is still limited. Current therapies aim to target programmed cell death (PD)-1 and programmed cell death ligand (PD-L)-1 in order to boost T cell activity. However, the role of the PD-1/PD-L1 axis during Leishmania infection is still unclear. In this study, we found that patients with active and post-treatment CL displayed different subsets of CD4+PD-1+ T cells. Accordingly, L. major-infected mice upregulated PD-1 on activated CD4+ T effector cells and PD-L1 on resident macrophages and infiltrating monocytes at the site of infection. L. major-infected Pdl1 -/- mice expressed lower levels of MHCII and higher levels of CD206 on macrophages and monocytes and, more importantly, the lack of PD-L1 contributed to a reduced frequency of CD4+Ly6Chi T effector cells and an increase of CD4+Foxp3+ regulatory T cells at the site of infection and in draining lymph nodes. Additionally, the lack of PD-L1 was associated with lower production of IL-27 by infiltrating monocytes and lower levels of the Th1 cytokines IFN-γ and TNF-α produced by CD4+ T effector cells. Pdl1 -/- mice initially exhibited larger lesions despite having a similar parasite load. Our results describe for the first time how the interruption of the PD-1/PD-L1 axis influences the immune response against CL and suggests that this axis regulates the balance between CD4+Ly6Chi T effector cells and CD4+Foxp3+ regulatory T cells.

| S-EPMC7642203 | 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