Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

IL-2 and IL-15 drive intrathymic differentiation of functionally distinct regulatory T lymphocyte-clusters

ABSTRACT: Intrathymic development of Foxp3-expressing regulatory T lymphocytes (Treg) depends on signals from the TCR, cytokine-receptors, and other cell-surface receptors. The cytokines IL-2 and IL-15 have been suggested to quantitatively modulate Treg-development. However, recent evidence showed that very large proportions of thymic Treg are cells that had migrated from the periphery back to the thymus. It remained therefore unclear if IL-2 and IL-15 quantitatively control the development of Treg. Moreover, these cytokines may also contribute to the differentiation of functionally distinct Treg subsets. Using an experimental setting in which we unambiguously distinguish newly developing from recirculating Treg, we here address the quantitative and qualitative roles of IL-2 and IL-15 in Treg-development, selection, and differentiation. Our results definitively demonstrate that in absence of IL-2 or IL-15 the thymus produces substantially less Treg. Importantly, IL-2 and IL-15 drive the differentiation of transcriptionally and phenotypically distinct Treg clusters, the number of which is substantially higher than previously appreciated. These cytokines also differentially modulate the TCR-repertoire expressed by newly developing Treg. Adoptive transfer of Treg from wt, IL-2- or IL-15-deficient animals into Treg-deficient new-born Scurfy mice, revealed differences in the in vivo function of these cells. Combined, our results indicate that IL-2 and IL-15 drive the development of functionally complementary Treg clusters.

ORGANISM(S): Mus musculus

PROVIDER: GSE154140 | GEO | 2025/07/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytes

Project description:Development of Foxp3-expressing regulatory T-lymphocytes (Treg) in the thymus is controlled by signals delivered in T-cell precursors via the TCR, co-stimulatory receptors, and cytokine receptors. In absence of IL-2, IL-15 or their receptors, fewer Treg apparently develop in the thymus. However, it was recently shown that a substantial part of thymic Treg are cells that had recirculated from the periphery back to the thymus, troubling interpretation of these results. We therefore reassessed the involvement of IL-2 and IL-15 in the development of Treg, taking into account Treg-recirculation. In three-week-old mice, when substantial amounts of recirculating Treg are present in the thymus, we found similarly reduced proportions of newly developed Treg in absence of IL-2 or IL-15, and in absence of both cytokines even less Treg developed. In neonates, when practically no recirculating Treg were found in the thymus, the absence of IL-2 led to substantially more reduced Treg-development than deficiency in IL-15. IL-2 and IL-15 differentially modulated the CD25, GITR, OX40, and CD73-phenotypes of thymus-egress-competent and periphery-seeding Treg. Interestingly, IL-2 and IL-15 also modulated the TCR-repertoire expressed by developing Treg. Upon transfer into Treg-less Foxp3sf mice, thymus-exit-competent Treg from IL-2- (and to a lesser extent IL-15-) deficient mice suppressed immunopathology less efficiently than wt Treg. Taken together, our results firmly establish important non-redundant quantitative and qualitative roles for IL-2 and, to a lesser extent, IL-15 in intrathymic Treg-development.

2022-08-29 | GSE153484 | GEO

Proteomics of Day 6 IL-2 or IL-15 expanded wild-type and Pim1/Pim2 double knockout CD8+ T cells.

Project description:T cell antigen-receptor (TCR) and cytokine receptor engagement trigger large changes in Serine/Threonine kinase signalling networks to drive T cell activation and differentiation. The role of only few kinase signalling pathways have been studied in detail, and in this context, Pim kinases are an interesting, yet understudied, family of Serine/Threonine kinases, with reported roles in key processes including survival, proliferation, metabolism across a range of cell types. T lymphocytes predominantly express PIM1 and PIM2, which are rapidly induced by TCR, costimulation and cytokine signalling. Using high-resolution mass spectrometry and RNAseq we systematically examine the impact of Pim1/Pim2 double deficiency on in vitro differentiated cytotoxic T lymphocytes (CTL) expanded in the cytokines IL-2 and IL-15 to generate effector or memory T cells respectively. We find that Pim kinases are dispensable for IL-15-driven memory cell differentiation, but that Pim1/2-deficiency has a selective impact on the transcriptome and proteome of IL-2 driven effector CD8 T cells. ~75% of Pim kinase-regulated proteins were not predicted by differences in mRNA in IL-2 expanded CTL. These included proteins that are key for effector cell function: glucose transporters SLC2A1 and SLC2A3 and key effector molecules Granzyme A and B. We find that Pim kinases have this effect via control of protein translation. Another key finding was that the mRNA for key T cell homing receptors Ccr7, S1pr1 and CD62L was increased in Pim1/2-deficienct T cells and that this functionally enhancing homing to secondary lymphoid organs.

2024-04-15 | PXD051213 | Pride

Characterization of receptor-associated protein complex assembly in Interleukin (IL)-2- and IL-15-activated T-lymphocytes

Project description:Despite extensive investigation, it remains a paradox that IL-2 and IL-15 can differentially modulate the immune response using the same signaling receptors. In our previous work, we dissected the phosphotyrosine-driven signaling cascades triggered by both cytokines in Kit225 T-cells unveiling subtle differences that may contribute to their functional dichotomy. In the present study, we aimed to decipher the receptor complex assembly in IL-2- and IL-15-activated T-lymphocytes that is fine tune orchestrated by site-specific phosphorylation events. Comparing the cytokine-induced interactome of the interleukin receptor beta and gamma subunits shared by the two cytokines, we defined the components of the early IL-2 and IL-15 receptor-associated complex discovering novel constituents such as FAM59A and SOCS2. Additionally, phosphopeptide-directed analysis allowed us to detect several cytokine-dependent and –independent phosphorylation events within the activated receptor complex including novel phosphorylated sites located in the cytoplasmic region of IL-2Rβ. We proved that the distinct phosphorylations induced by the cytokines serve for recruiting different types of effectors to the initial receptor/ligand complex. Whereas IL-2Rβ pS431 binds to clathrins, which are involved in the receptor internalization and subsequent signal attenuation, IL-2Rγ pY325 and pY357 attract phosphatases, adaptor proteins, kinases as well as the newly identified member of the interleukin receptor complex SOCS2. Overall our study sheds new light into the initial molecular mechanisms triggered by IL-2 and IL-15 and constitutes a further step towards a better understanding of the early signaling aspects of the two closely-related cytokines in T-lymphocytes.

2016-08-08 | PXD002386 | Pride

Dissection of IL-2 and IL-15 signaling pathways

Project description:The aim of this study was to compare the signaling cascades initiated by the two closely related cytokines IL-2 and IL-15. Considering the relevance of protein tyrosine phosphorylation in signal transduction, in order to quantify changes in protein phosphorylation in response to IL-2 and IL-15, we combined triple SILAClabeling of leukemic T-cells with phosphotyrosine (pY)-specific antibody-based protein enrichment followed by mass spectrometry (MS) analysis. Following the strategy described above, we managed to decipher in detail the complex signaling networks triggered by IL-2 and IL-15. Interestingly, a large number of components of the three main signaling pathways known to be initiated in response to the interleukins (JAK/STAT; RAS/MAPK; PI3K/AKT) were identified.

2014-09-23 | PXD001129 | Pride

Characterization of receptor-associated protein complex assembly in Interleukin (IL)-2- and IL-15-activated T-lymphocytes

Project description:Despite extensive investigation, it remains a paradox that IL-2 and IL-15 can differentially modulate the immune response using the same signaling receptors. In our previous work, we dissected the phosphotyrosine-driven signaling cascades triggered by both cytokines in Kit225 T-cells unveiling subtle differences that may contribute to their functional dichotomy. In the present study, we aimed to decipher the receptor complex assembly in IL-2- and IL-15-activated T-lymphocytes that is fine tune orchestrated by site-specific phosphorylation events. Comparing the cytokine-induced interactome of the interleukin receptor beta and gamma subunits shared by the two cytokines, we defined the components of the early IL-2 and IL-15 receptor-associated complex discovering novel constituents such as FAM59A and SOCS2. Additionally, phosphopeptide-directed analysis allowed us to detect several cytokine-dependent and –independent phosphorylation events within the activated receptor complex including novel phosphorylated sites located in the cytoplasmic region of IL-2R?. We proved that the distinct phosphorylations induced by the cytokines serve for recruiting different types of effectors to the initial receptor/ligand complex. Whereas IL-2R? pS431 binds to clathrins, which are involved in the receptor internalization and subsequent signal attenuation, IL-2R? pY325 and pY357 attract phosphatases, adaptor proteins, kinases as well as the newly identified member of the interleukin receptor complex SOCS2. Overall our study sheds new light into the initial molecular mechanisms triggered by IL-2 and IL-15 and constitutes a further step towards a better understanding of the early signaling aspects of the two closely-related cytokines in T-lymphocytes.

2017-03-31 | MSV000080850 | MassIVE

Dissection of IL-2 and IL-15 signaling pathways

2017-03-29 | MSV000080767 | MassIVE

PD-1 restrains thymic IL-2 production and regulatory T cell development

Project description:Inhibitory proteins, such as programmed cell death protein 1 (PD-1), have been extensively studied in peripheral T cell responses to foreign, self, and neoantigens. Notably, these proteins are first expressed during T cell development in the thymus. Reports suggest that PD-1 limits regulatory T cell (Treg) development, but the mechanism by which PD-1 exerts this function remains unknown. The present study expands the evaluation of PD-1 and its ligands in the thymus, demonstrating that some of the highest expressers of PD-1 and PD-L1 are agonist selected cells. Surprisingly, we reveal a selective role for PD-1 in regulating the developmental niche only for Tregs as other agonist selected cell populations, such as natural killer T cells, remain unchanged. We also ruled out PD-1 as a regulator of proliferation or cell death of agonist selected Tregs and further demonstrated that PD-1 deficient Tregs have reduced TCR signaling. Unexpectedly, the data suggests that PD-1 deficient thymocytes produce elevated levels of IL-2, a Treg niche limiting cytokine. Collectively, these data suggest a novel role for PD-1 in regulating IL-2 production and the concurrent agonist selection of thymic Tregs. This observation has implications for the use of checkpoint blockade in the context of cancer and infection.

2024-02-19 | GSE255727 | GEO

Attenuated IL-2 muteins promote regulatory T cell adaptation of the effector phenotype and function in vivo via modified IL-2 responses

Project description:Interleukin-2 (IL-2), along with T-cell receptor (TCR) signaling, are required to control regulatory T cell (Treg) homeostasis and function in vivo. Due to the heightened sensitivity to IL-2, Tregs retain the ability to respond to low-dose or attenuated forms of IL-2, as currently being developed for clinical use to treat inflammatory diseases. While attenuated IL-2 increases Treg selectivity, the question remains as to whether a weakened IL-2 signal sufficiently enhances Treg suppressive function(s) toward disease modification. To understand this question, we characterized the in vivo activity and transcriptomic profiles of two different attenuated IL-2 muteins in comparison with wildtype (WT) IL-2. Our study showed that, in addition to favoring Tregs, the attenuated muteins induced disproportionately robust effects on Treg activation and conversion to effector Treg (eTreg) phenotype. Our data furthermore suggested that Tregs activated by attenuated IL-2 muteins showed reduced dependence on TCR signal, at least in part due to the enhanced ability of IL-2 muteins to amplify the TCR signal in vivo. These results point to a new paradigm wherein IL-2 influences Tregs’ sensitivity to antigenic signal, and that the combination effect may be leveraged for therapeutic use of attenuated IL-2 muteins.

2023-09-05 | GSE216130 | GEO

Cooperative armoring of CAR and TCR T-cells by T cell-restricted IL-15 and IL-21 universally enhances solid tumor efficacy

Project description:Chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies are effective in a subset of patients with solid tumors, but new approaches are needed to enhance efficacy and universally improve patient outcomes. IL-15 and IL-21 are common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T-cells and other lymphocytes. We found that self-delivery of these cytokines by CAR or TCR T-cells prevents functional exhaustion by repeated stimulation and limits the emergence of dysfunctional natural killer (NK)-like T-cells. Across different preclinical murine solid tumor models, we observe enhanced regression with each individual cytokine but the greatest anti-tumor efficacy when T-cells are armored with both. Thus, the co-expression of membrane-tethered IL-15 and IL-21 represents a technology to enhance the resilience and function of engineered T-cells against solid tumors and could be applicable to multiple therapy platforms and diseases.

2023-08-29 | GSE229651 | GEO

Essential and non-overlapping IL-2Rα-dependent signaling for thymic development and peripheral homeostasis of regulatory T cells

Project description:IL-2R signaling is essential for regulatory T cell (Treg) function. However, the precise contribution for IL-2 during Treg thymic development, peripheral homeostasis, and lineage stability remains unclear. Here we show that IL-2R signaling is essential for thymic Tregs at an early step for expansion/survival and a later step for functional maturation. Using selective deletion of CD25 in peripheral Tregs, we also find that IL-2R signaling was absolutely essential for their persistence whereas Treg lineage stability was IL-2-independent. CD25 knockout peripheral Tregs showed increased apoptosis, oxidative stress, signs of mitochondrial dysfunction, and reduced transcription of key enzymes of lipid and cholesterol biosynthetic pathways. A divergent IL-2 transcriptional signature was noted for thymic Tregs versus peripheral Tregs. These data indicate that IL-2R signaling in the thymus and the periphery leads to distinctive effects on Treg function, where peripheral Treg survival depends on a non-conventional mechanism of metabolic regulation.

2019-02-01 | GSE121883 | GEO

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