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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

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.

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Bach2 attenuates IL-2R signalling to control Treg homeostasis and Tfr development

Project description:Differentiation and homeostasis of Foxp3 + regulatory T cells (Tregs) are tightly controlled by the interleukin-2 receptor (IL-2R) signaling, yet the mechanisms governing these processes are incompletely understood. Here we report that transcription factor Bach2 attenuates IL-2R signaling to coordinate Treg differentiation and homeostasis by directly repressed CD25 (IL-2Rα). Thus, Bach2 balances IL-2R signaling to orchestrate development and homeostasis of various Treg subsets.

2021-05-11 | GSE164937 | 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.

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Rank pathway activation attenuates mammary tumorigenesis by inducing senescence

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2022-02-24 | GSE139675 | GEO

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

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

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Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22

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