Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Thymic DCs derived IL-27 regulates the final maturation of CD4(+) SP thymocytes.

ABSTRACT: IL-27, as a pleiotropic cytokine, promotes the differentiation of naïve T cells to Th1, while suppressing Th2 and Th17 differentiation in the periphery. However, the role of IL-27 in the thymocyte development remains unknown. Here we showed that IL-27 was highly expressed in thymic plasmacytoid dendritic cells (pDCs) while its receptor expression was mainly detected in CD4(+) single-positive (SP) thymocytes. Deletion of the p28 subunit in DCs resulted in a reduction of the most mature Qa-2(+) subsets of CD4(+) SP T cells. This defect was rescued by intrathymic administration of exogenous IL-27. In vitro differentiation assay further demonstrated that IL-27 alone was able to drive the maturation of the newly generated 6C10(+)CD69(+)CD4(+) SP cells into Qa-2(+) cells. Collectively, this study has revealed an important role of thymic DCs-derived IL-27 in the regulation of the phenotypic maturation of CD4(+) SP thymocytes.

SUBMITTER: Tang H

PROVIDER: S-EPMC5387111 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Thymic DCs derived IL-27 regulates the final maturation of CD4(+) SP thymocytes.

Tang Hui H Zhang Jie J Sun Xiuyuan X Qian Xiaoping X Zhang Yu Y Jin Rong R

Scientific reports 20160729

IL-27, as a pleiotropic cytokine, promotes the differentiation of naïve T cells to Th1, while suppressing Th2 and Th17 differentiation in the periphery. However, the role of IL-27 in the thymocyte development remains unknown. Here we showed that IL-27 was highly expressed in thymic plasmacytoid dendritic cells (pDCs) while its receptor expression was mainly detected in CD4(+) single-positive (SP) thymocytes. Deletion of the p28 subunit in DCs resulted in a reduction of the most mature Qa-2(+) su ...[more]

PMID: 27469302

Similar Datasets

Thymic exosomes promote the final maturation of thymocytes.

Project description:Extensive knowledge has been gained the last years concerning mechanisms underlying the selection of single positive thymocytes in the thymic medulla. Less is known regarding other important processes in the thymic medulla such as the regulation of late stage thymocyte maturation. We have previously reported that exosomes are abundant in the thymus with a phenotype that indicates an epithelial cell origin and immunoregulatory properties. In this study we use an in vitro system to investigate the effects of thymic exosomes on the maturation of single positive thymocytes as well as effects on nTreg formation. We show that thymic exosomes promote the maturation of single positive CD4(+)CD25(-) cells into mature thymocytes with S1P1(+)Qa2(+) and CCR7(+)Qa2(+) phenotypes. Furthermore, we show that thymic exosomes reduce the formation of CD4(+)CD25(+)FoxP3(+) thymocytes and that these exosome effects are independent of dendritic cell co-stimulation but require intact exosomal RNA content and surface proteins. An efficient direct uptake of exosomes by both thymocytes and thymic DC's is also demonstrated. In conclusion, this study demonstrates that exosomes may represent a new route of communication within the thymus.

| S-EPMC5099897 | biostudies-other

The molecular signature underlying the thymic migration and maturation of TCRαβ+ CD4+ CD8 thymocytes.

Project description:BackgroundAfter positive selection, the newly generated single positive (SP) thymocytes migrate to the thymic medulla, where they undergo negative selection to eliminate autoreactive T cells and functional maturation to acquire immune competence and egress capability.Methodology/principal findingsTo elucidate the genetic program underlying this process, we analyzed changes in gene expression in four subsets of mouse TCRαβ(+)CD4(+)CD8(-) thymocytes (SP1 to SP4) representative of sequential stages in a previously defined differentiation program. A genetic signature of the migration of thymocytes was thus revealed. CCR7 and PlexinD1 are believed to be important for the medullary positioning of SP thymocytes. Intriguingly, their expression remains at low levels in the newly generated thymocytes, suggesting that the cortex-medulla migration may not occur until the SP2 stage. SP2 and SP3 cells gradually up-regulate transcripts involved in T cell functions and the Foxo1-KLF2-S1P(1) axis, but a number of immune function-associated genes are not highly expressed until cells reach the SP4 stage. Consistent with their critical role in thymic emigration, the expression of S1P(1) and CD62L are much enhanced in SP4 cells.ConclusionsThese results support at the molecular level that single positive thymocytes undergo a differentiation program and further demonstrate that SP4 is the stage at which thymocytes acquire the immunocompetence and the capability of emigration from the thymus.

| S-EPMC3192722 | biostudies-literature

CD40 Mediates Maturation of Thymic Dendritic Cells Driven by Self-Reactive CD4+ Thymocytes and Supports Development of Natural Regulatory T Cells.

Project description:Thymic dendritic cells (tDCs) play an important role in central tolerance by eliminating self-reactive thymocytes or differentiating them to regulatory T (Treg) cells. However, the molecular and cellular mechanisms underlying these functions are not completely understood. We found that mouse tDCs undergo maturation following cognate interaction with self-reactive CD4+ thymocytes and that this maturation is dependent on CD40 signaling. Ablation of CD40 expression in tDCs resulted in a significant reduction in the number of Treg cells in association with a significant reduction in the number of mature tDCs. In addition, CD40-deficient DCs failed to fully mature upon cognate interaction with CD4+ thymocytes in vitro and failed to differentiate them into Treg cells to a sufficient number. These findings suggest that tDCs mature and potentiate Treg cell development in feedback response to self-reactive CD4+ thymocytes.

| S-EPMC5809249 | biostudies-literature

Antigen recognition by autoreactive CD4⁺ thymocytes drives homeostasis of the thymic medulla.

Project description:The thymic medulla is dedicated for purging the T-cell receptor (TCR) repertoire of self-reactive specificities. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process because they express numerous peripheral tissue-restricted self-antigens. Although it is well known that medulla formation depends on the development of single-positive (SP) thymocytes, the mechanisms underlying this requirement are incompletely understood. We demonstrate here that conventional SP CD4⁺ thymocytes bearing autoreactive TCRs drive a homeostatic process that fine-tunes medullary plasticity in adult mice by governing the expansion and patterning of the medulla. This process exhibits strict dependence on TCR-reactivity with self-antigens expressed by mTECs, as well as engagement of the CD28-CD80/CD86 costimulatory axis. These interactions induce the expression of lymphotoxin α in autoreactive CD4⁺ thymocytes and RANK in mTECs. Lymphotoxin in turn drives mTEC development in synergy with RANKL and CD40L. Our results show that Ag-dependent interactions between autoreactive CD4⁺ thymocytes and mTECs fine-tune homeostasis of the medulla by completing the signaling axes implicated in mTEC expansion and medullary organization.

| S-EPMC3531460 | biostudies-literature

cDC1-derived IL-27 regulates small intestinal CD4+ T cell homeostasis in mice.

Project description:The small intestinal lamina propria contains large numbers of IFNγ-producing T helper (Th1) cells that play important roles in intestinal homeostasis and host defense, but the mechanisms underlying their development remain poorly understood. Here, we demonstrate that Th1 cells accumulate in the SI-LP after weaning and are maintained there long term. While both Th17 and Th1 cell accumulation in the SI-LP was microbiota dependent, Th1 cell accumulation uniquely required IL-27 and MHCII expression by cDC1. This reflected a requirement for IL-27 signaling in the priming of Th1 cells rather than for their maintenance once in the mucosa. cDC1-derived IL-27 was essential for maintaining the Th1-Th17 balance within the SI-LP, and in its absence, remaining Th1 cells expressed enhanced levels of Th17 signature genes. In conclusion, we identify cDC1-derived IL-27 as a key regulator of SI-LP Th1-Th17 cell homeostasis.

| S-EPMC9754766 | biostudies-literature

IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms.

Project description:IL-27, a novel heterodimeric cytokine produced by antigen-presenting cells, signals through the T cell cytokine receptor (TCCR)/WSX-1 expressed on naïve CD4+ T cells and natural killer cells. TCCR/WSX-1 deficiency results in delayed T helper type 1 (TH1) development through an unresolved mechanism. We report here that IL-27 stimulation in developing murine T helper cells potently induces the expression of the major TH1-specific transcription factor T-bet and its downstream target IL-12R beta2, independently of IFN gamma. In addition, IL-27 suppresses basal expression of GATA-3, the critical TH2-specific transcription factor that inhibits TH1 development by down-regulating signal transducer and activator of transcription (Stat) 4. IL-27 signaling through TCCR/WSX-1 induces phosphorylation of Stat1, Stat3, Stat4, and Stat5. Stat1 is required for suppression of GATA-3, but T-bet induction by IL-27 can also be mediated through a Stat1-independent pathway. Despite its TH1-like signaling profile, IL-27 is not sufficient to drive the differentiation of CD4+ T cells into IFN gamma-producing cells. Similarly, IL-27 induces T-bet expression in primary natural killer cells, but this does not result in an increase of IFN gamma production or cytotoxic activity. Therefore, although IL-27 is unable to drive IFN gamma production on its own, it plays an important role in the early steps of TH1 commitment by contributing in a paracrine manner to the control of IL-12 responsiveness.

| S-EPMC299900 | biostudies-other

IL-27 produced during acute malaria infection regulates Plasmodium-specific memory CD4+ T cells

Project description:Malaria infection elicits both protective and pathogenic immune responses, and IL-27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4+ T cell responses that is targeted by IL-27. Neutralization of IL-27 during acute infection with Plasmodium chabaudi expanded specific CD4+ T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium-specific CD4+ T cells in IL-27-neutralized mice consisted mainly of CD127+KLRG1- and CD127-KLRG1+ subpopulations that displayed distinct cytokine production, proliferative capacity and are maintained in a manner independent of active infection. Single cell RNA-seq analysis revealed that these CD4+ T cell subsets formed independent clusters that express unique Th1-type genes. These IL-27-neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL-27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4+ T cells, suggesting potential implications for the development of vaccines and other strategic interventions.

| S-SCDT-10_15252-EMMM_202317713 | biostudies-other

Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis.

Project description:The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.

| S-EPMC10179146 | biostudies-literature

The IL-27 receptor regulates TIGIT on memory CD4<sup>+</sup> T cells during sepsis.

Project description:Sepsis is a leading cause of morbidity and mortality associated with significant impairment in memory T cells. These changes include the upregulation of co-inhibitory markers, a decrease in functionality, and an increase in apoptosis. Due to recent studies describing IL-27 regulation of TIGIT and PD-1, we assessed whether IL-27 impacts these co-inhibitory molecules in sepsis. Based on these data, we hypothesized that IL-27 was responsible for T cell dysfunction during sepsis. Using the cecal ligation and puncture (CLP) sepsis model, we found that IL-27Rα was associated with the upregulation of TIGIT on memory CD4+ T cells following CLP. However, IL-27 was not associated with sepsis mortality.

| S-EPMC7881227 | biostudies-literature

IL-27 produced during acute malaria infection regulates Plasmodium-specific memory CD4<sup>+</sup> T cells.

Project description:Malaria infection elicits both protective and pathogenic immune responses, and IL-27 is a critical cytokine that regulate effector responses during infection. Here, we identified a critical window of CD4+ T cell responses that is targeted by IL-27. Neutralization of IL-27 during acute infection with Plasmodium chabaudi expanded specific CD4+ T cells, which were maintained at high levels thereafter. In the chronic phase, Plasmodium-specific CD4+ T cells in IL-27-neutralized mice consisted mainly of CD127+ KLRG1- and CD127- KLRG1+ subpopulations that displayed distinct cytokine production, proliferative capacity, and are maintained in a manner independent of active infection. Single-cell RNA-seq analysis revealed that these CD4+ T cell subsets formed independent clusters that express unique Th1-type genes. These IL-27-neutralized mice exhibited enhanced cellular and humoral immune responses and protection. These findings demonstrate that IL-27, which is produced during the acute phase of malaria infection, inhibits the development of unique Th1 memory precursor CD4+ T cells, suggesting potential implications for the development of vaccines and other strategic interventions.

| S-EPMC10701605 | 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