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Intrinsic IL-2 Production by Effector CD8 T Cells Attenuates IL-2-signalling and Promotes Fate Decisions, Stemness, and Viral Protection

ABSTRACT: Intrinsic IL-2 Production by Effector CD8 T Cells Attenuates IL-2-signalling and Promotes Fate Decisions, Stemness, and Viral Protection

PROVIDER: PRJNA566383 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10145226_1.fastq.gz	Fastqsanger.gz
	SRR10145226_2.fastq.gz	Fastqsanger.gz
	SRR10145227_1.fastq.gz	Fastqsanger.gz
	SRR10145227_2.fastq.gz	Fastqsanger.gz
	SRR10145228_1.fastq.gz	Fastqsanger.gz

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Intrinsic IL-2 Production by Effector CD8 T Cells Attenuates IL-2-signalling and Promotes Fate Decisions, Stemness, and Viral Protection

Project description:Interleukin-2 (IL-2) plays pivotal roles in directing the differentiation of effector and memory CD8 T cells; nevertheless, the contributions of IL-2 synthesis by CD8 T cells versus sensitivity to IL-2 signals in shaping their developmental fates and protective efficacy is less clear. Here we show that, rather than acting in an autocrine manner, the production of IL-2 by CD8 T cells restricts their ability to receive STAT5-dependent IL-2 signals, and the capacity to manufacture IL-2 delineates constituents of the expanded effector pool that display stem-like features, preferentially survive, more rapidly attain memory traits, and control chronic viral challenges. Despite having distinct properties during the effector phase, IL-2-producing and non-producing CD8 T cells phenotypically coalesce as memory matures to form populations with equal recall abilities. Therefore, the potential to produce IL-2 during the effector but not memory phase is a consequential cellular feature that dictates the protective capabilities of the response.

2022-01-17 | GSE137717 | GEO

Intrinsic IL-2 production by effector CD8 T cells affects IL-2 signaling and promotes fate decisions, stemness, and protection.

Project description:Here, we show that the capacity to manufacture IL-2 identifies constituents of the expanded CD8 T cell effector pool that display stem-like features, preferentially survive, rapidly attain memory traits, resist exhaustion, and control chronic viral challenges. The cell-intrinsic synthesis of IL-2 by CD8 T cells attenuates the ability to receive IL-2-dependent STAT5 signals, thereby limiting terminal effector formation, endowing the IL-2-producing effector subset with superior protective powers. In contrast, the non-IL-2-producing effector cells respond to IL-2 signals and gain effector traits at the expense of memory formation. Despite having distinct properties during the effector phase, IL-2-producing and nonproducing CD8 T cells appear to converge transcriptionally as memory matures to form populations with equal recall abilities. Therefore, the potential to produce IL-2 during the effector, but not memory stage, is a consequential feature that dictates the protective capabilities of the response.

| S-EPMC8923238 | biostudies-literature

Attenuated IL-2 Signaling Rewires Transcriptional and Metabolic Programs in T Cells to Enable Coupling Proliferation and Stemness

Project description:Interleukin-2 (IL-2) is a fundamental cytokine that controls the proliferation and differentiation of T cells1. Its direct administration in vivo has conferred durable, complete responses in patients with metastatic melanoma and renal cell cancer, while it is also used to expand tumor-infiltrating lymphocytes (TILs) in vitro for adoptive cell therapy (ACT)2. Unfavorable properties of IL-2 including terminal differentiation of effector T cells3-6, induction of activation-induced cell death (AICD)2, 7, 8, expansion of regulatory T (Treg) cells, and toxicity at high doses, have driven the development of IL-2 variants with modified biological properties9-13. However, how cytokine modifications alter cell fate decisions is not well understood. Here, taking a systems biology approach we have comprehensively elucidated how a non CD25-binding, IL-2-biased agonist (IL-2v)14 reprograms signaling, transcriptional, and metabolic networks of CD8+ T cells in vitro to favor stemness while simultaneously driving expansion and functionality. Such "expansion-stemness state" defines metabolically fit CD8+ T cells capable of superior persistence and tumor control. These findings broaden our fundamental understanding of the effects of IL-2v on T-cell biology and provide an investigational framework for the rational development and evaluation of cytokine variants with clinical relevance.

2025-01-01 | GSE223651 | GEO

Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

Project description:Piezo2 impedes stemness maintenance of CD8+ T cells by downregulating IL-15 production after radiotherapy, thereby leading to cancer radioresistance.

2024-08-08 | GSE236345 | GEO

Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

Project description:Piezo2 impedes stemness maintenance of CD8+ T cells by downregulating IL-15 production after radiotherapy, thereby leading to cancer radioresistance.

2024-08-08 | GSE236339 | GEO

IL-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration

Project description:Necrotizing enterocolitis (NEC) is a devastating intestinal inflammatory disorder that primarily affects premature infants. Despite decades of research, this disease remains a significant cause of death in the absence of efficient therapeutics. Interleukin (IL)-22 has been shown to play a critical role in maintaining the gut barrier, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models with an established microbiome. However, the importance of IL-22 signaling in the regulation of gut homeostasis and protection in neonates that lack an established microbiome remains unknown. Therefore, the aim of the current study is to investigate the role of IL-22 in the neonatal intestinal epithelium under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal that Il22 expression in neonatal murine intestine is negligible until weaning. In addition, both human and murine neonates lack IL-22 production during NEC. Mice deficient in IL-22 or mice lacking the expression of IL-22 receptor in intestinal epithelial cells, display a similar susceptibility of neonates to NEC consistent with the lack of endogenous IL-22 at this critical stage of intestinal development. Conversely, treatment with recombinant IL-22 during NEC substantially reduces disease severity. This IL-22-mediated protection is associated with enhanced epithelial regeneration and increased expression of several antimicrobial genes. Strikingly, despite an IL-22-mediated induction of an antimicrobial transcriptional program, the composition of the intestinal microbial communities remains unchanged. Taken together, this study demonstrates that an IL-22 signaling axis promotes protection against neonatal NEC through the induction of epithelial cell regeneration.

2021-05-18 | GSE155172 | GEO

Effect of temperature protection on postoperative immune function in elderly patients with colorectal cancer

Project description:Interventions: Body temperature Protection group (T group):Intraoperative routine temperature protection+Inflatable heating system;Control group (C Group):Intraoperative routine temperature protection Primary outcome(s): interleukin 17 (IL17);transforming growth factor-ß (TGF-ß);Interleukin- 6 (IL-6);Intraoperative core body temperature;Incidence of postoperative complications;Lymphocyte count Study Design: Parallel

| 2699857 | ecrin-mdr-crc

An engineered IL-2 partial agonist promotes CD8+ T cell stemness

Project description:An engineered IL-2 partial agonist promotes CD8+ T cell stemness

| PRJNA576860 | ENA

Inhibition of IL-6 signaling attenuates vascular damage caused by HIF1α activation

Project description:Protection against endothelial damage is recognized as a frontline approach to preventing the progression of cytokine release syndrome (CRS). Accumulating evidence has demonstrated that interleukin-6 (IL-6) promotes vascular endothelial damage during CRS, although the molecular mechanisms remain to be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition of the immune system. Here, we show that endothelial IL-6 trans-signaling promoted vascular damage and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)‒induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R‒HIF1α signaling in endothelial cells protected against vascular injury caused by septic damage and provided survival benefit in a mouse model of sepsis. In addition, we developed a short half-life anti-IL-6R antibody (silent anti-IL-6R antibody) and found that it was highly effective at augmenting survival for sepsis and severe burn by strengthening the endothelial glycocalyx and reducing cytokine storm, and vascular leakage. Together, our data advance the role of endothelial IL-6 trans-signaling in the progression of CRS and indicate a potential therapeutic approach for burns to address the lack of burn-specific treatments.

2023-12-18 | GSE241139 | GEO

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation

Project description:The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.

2024-07-01 | GSE248348 | GEO

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