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

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

PROVIDER: PRJNA498889 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8117650_1.fastq.gz	Fastqsanger.gz
	SRR8117650_2.fastq.gz	Fastqsanger.gz
	SRR8117660_1.fastq.gz	Fastqsanger.gz
	SRR8117660_2.fastq.gz	Fastqsanger.gz
	SRR8117651_1.fastq.gz	Fastqsanger.gz

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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

Essential and non-overlapping IL-2Rα-dependent processes 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 of IL-2 during Treg thymic development, peripheral homeostasis and lineage stability remains unclear. Here we show that IL-2R signaling is required by thymic Tregs at an early step for expansion and survival, and a later step for functional maturation. Using inducible, conditional deletion of CD25 in peripheral Tregs, we also find that IL-2R signaling is indispensable for Treg homeostasis, whereas Treg lineage stability is largely IL-2-independent. CD25 knockout peripheral Tregs have increased apoptosis, oxidative stress, signs of mitochondrial dysfunction, and reduced transcription of key enzymes of lipid and cholesterol biosynthetic pathways. A divergent IL-2R transcriptional signature is 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, while peripheral Treg survival depends on a non-conventional mechanism of metabolic regulation.

| S-EPMC6399264 | biostudies-literature

RNA-sequencing of livers from p40-/-IL-2Rα-/- PBC mouse model and control.

Project description:We performed RNA sequencing of liver transcriptome from 12-week-old p40-/-IL-2Rα-/- (a mouse model of primary biliary cholangitis) and littermate p40-/-IL-2Ra+/- (control) mice.

2021-09-16 | GSE184066 | GEO

A PD-1-targeted, receptor-masked IL-2 immunocytokine that engages IL-2Rα strengthens T cell-mediated anti-tumor therapies

Project description:IL-2 is a cytokine approved for the treatment of melanoma and renal cell carcinoma and induced complete, durable tumor regression in some patients. However, its broader use in cancer immunotherapy has been limited by severe toxicity. A new generation of IL-2 therapies with decreased binding to IL-2 receptor alpha chain (IL-2Rα), intended to mitigate toxicity and Treg expansion, are being developed. However to date these have had limited clinical success. Here, we demonstrate that the ability to engage IL-2Rα is critical for the anti-tumor activity of a systemic IL-2 therapy. Despite inducing systemic expansion of CD8+ T cells and NK cells over Tregs, an IL-2 mutein with abolished IL-2Rα binding demonstrated limited anti-tumor efficacy compared to wild-type IL-2. Based on these findings, we developed a PD-1-targeted, receptor-masked IL-2 immunocytokine, PD1-IL2Ra-IL2, with attenuated systemic IL-2 activity but maintained the capacity to engage IL-2Rα on PD-1+ T cells. PD1-IL2Ra-IL2 (REGN10597) shows PD-1-targeting-dependent IL-2 activity in vitro and drives selective expansion of tumor-infiltrating PD-1+ CD8+ T cells with vigorous effector profiles in vivo. PD1-IL2Ra-IL2 treated mice displayed no signs of systemic toxicities observed with unmasked IL-2 treatment, yet achieved robust tumor growth control. Finally, we demonstrate that PD1-IL2Ra-IL2 can be effectively combined with several other T cell-mediated immunotherapies (anti-PD-1, CD3 bispecific antibodies, and CAR-T cells) to potentiate antitumor responses. Collectively, these results provide unique insights into the functional mechanism of IL-2 based therapeutics and highlight the therapeutic potential of PD1-IL2Ra-IL2 as a novel targeted, receptor masked, and “α-maintained” IL-2 therapy for cancer treatment.

2024-08-22 | GSE250205 | GEO

Non-overlapping functions for Notch1 and Notch3 during murine steady state thymic lymphopoiesis.

Project description:Notch1 signaling is absolutely essential for steady-state thymic lymphopoiesis, but the role of other Notch receptors, and their potential overlap with the function of Notch1, remains unclear. Here we show that like Notch1, Notch3 is differentially expressed by progenitor thymocytes, peaking at the DN3 progenitor stage. Using mice carrying a gene-trapped allele, we show that thymic cellularity is slightly reduced in the absence of Notch3, although progression through the defined sequence of TCR-αβ development is normal, as are NKT and TCRγδ cell production. The absence of a profound effect from Notch3 deletion is not explained by residual function of the gene-trapped allele, since insertion mapping suggests that the targeted allele would not encode functional signaling domains. We also show that although Notch1 and Notch3 are co-expressed on some early intrathymic progenitors, the relatively mild phenotype seen after Notch3 deletion does not result from the compensatory function of Notch1, nor does Notch3 function explain the likewise mild phenotype seen after conditional (intrathymic) deletion of Notch1. Our studies indicate that Notch1 and Notch3 carry out non-overlapping functions during thymocyte differentiation, and that while Notch1 is absolutely required early in the lymphopoietic process, neither receptor is essential at later stages.

2011-08-03 | GSE30631 | GEO

IL-2Rα is Dispensable for Murine B Cell Development and Humoral Response

Project description:The cytokine IL-2 plays a pivotal role in the immune system, specifically in the proliferation of T, B, and NK cells. The alpha subunit of the IL-2 receptor, IL-2Rα (CD25), is known to regulate the expansion and differentiation of T lymphocytes. CD25 is also expressed in developing B cells; however, its B cell intrinsic role remains undefined. We generated a mouse model with a B cell-specific deletion of CD25 to ascertain its role in B cell development and function. Unexpectedly, we found that the loss of CD25 had no impact on B cell development, homeostasis, or immune response to model antigens. Additionally, while CD25 expression was upregulated in activated splenic B cells, its absence did not affect class switch recombination in vitro or in vivo. We conclude that in contrast to its critical role in T cell differentiation and function, and despite its expression in developing and activated B cells, CD25 does not have any significant role in B cell development and adaptive immune functions.

2025-05-07 | GSE282135 | GEO

Broad and largely overlapping molecular changes arise in thymic and peripheral XCR1+ dendritic cells upon tolerogenic and immunogenic maturation

Project description:Broad and largely overlapping molecular changes arise in thymic and peripheral XCR1+ dendritic cells upon tolerogenic and immunogenic maturation

| PRJNA290486 | ENA

IL-2Rα is Dispensable for Murine B Cell Development and Humoral Response

Project description:IL-2Rα is Dispensable for Murine B Cell Development and Humoral Response

| PRJNA1187268 | ENA

RNA-sequencing of livers from p40-/-IL-2Rα-/- PBC mouse model and control.

Project description:RNA-sequencing of livers from p40-/-IL-2Rα-/- PBC mouse model and control.

| PRJNA763076 | ENA

Defining STAT5 target genes in thymic precursor cells at pre- and post-commitment stages

Project description:STAT5 is critical for inducing lineage specifying transcription factors, establishing effector gene programs, upregulating IL-2Rα (also known as CD25), and supporting cell survival in response to environmental cues in mature T cells. Although it has been shown that IL-7-induced STAT5 signaling is also essential for survival of thymic precursor cells, the exact roles of STAT5A and STAT5B and their target genes that contribute to the developmental program in early thymic development have been unknown. To define STAT5 target genes in these early T-cell progenitors, we have performed CRISPR-Cas9 mediated acute deletion of Stat5a and Stat5b in combination. We first carried out preliminary experiments to determine the stages in which IL-7 could induce maximal STAT5 phosphorylation in thymic double negative (DN) cells (B. Shin, unpublished data). We then focused on genes responding to loss of STAT5 in two different stages: CD25+ Bcl11b- pre-commitment stage, and CD25+ Bcl11b+ post-commitment stage. Of note, to generate these early pro-T cells in OP9-DLL1 coculture, we exploited bone-marrow precursor cells expressing a Bcl2 transgene to minimize survival defects due to loss of STAT5A and STAT5B. Our data show that STAT5 is necessary, in both pre- and post-commitment stages, for optimal expression of the IL-2Rα gene (Il2ra), which is constitutively expressed in normal DN2 and DN3 pro-T cells. This dataset further defines a distinct set of additional genes responding more strongly to loss of STAT5 in pro-T cells. The linked manuscript by R. Spolski et al. and other datasets referenced therein include data documenting the genomic occupancy of STAT5B in corresponding stages. In summary, our data define STAT5-responsive target genes during early T development.

2023-10-16 | GSE184845 | GEO

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