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An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells [10x scRNA-seq]

ABSTRACT: An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells [10x scRNA-seq]

PROVIDER: PRJNA1049369 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27109300.fastq.gz	Fastqsanger.gz
	SRR27109301.fastq.gz	Fastqsanger.gz
	SRR27109298.fastq.gz	Fastqsanger.gz
	SRR27109299.fastq.gz	Fastqsanger.gz

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An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells [10x scRNA-seq]

Project description:Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are under clinical investigation for treating autoimmune and inflammatory diseases. We previously described an Fc-fused CD25-biased IL-2 mutein (Fc.IL-2 mutein) that promotes TR expansion and prevents the onset of autoimmune diabetes in non-obese diabetic (NOD) mice; however, the effects of this treatment on TR function in vivo are unclear. Here we show that Fc.IL-2 mutein treatment induces an activated Foxp3+ TR population characterized by elevated proliferation, a unique transcriptional program associated with Stat5- and TCR-dependent gene modules, and high levels of the immunosuppressive molecules IL-10 and CTLA-4. Increased IL-10 receptor signaling limits the upregulation of surface MHC class II expression during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis leads to the transfer of CD80 and CD86 costimulatory ligands from maturing cDCs to Tregs. In NOD mice, Fc.IL-2 mutein treatment resulted in TR-mediated regulation of cDCs in the inflamed pancreas and draining lymph nodes accompanied by an increase in anergic T cells. Thus, we demonstrate that IL-2 mutein-expanded TR cells have enhanced functional properties and potently act to restrict cDC function in the target tissue and at the site of autoimmune induction, offering promising prospects for targeted immunotherapy.

2023-12-08 | GSE249481 | GEO

An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells [RNA-seq]

Project description:Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3+ regulatory T (TR) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated TR population with elevated proliferation, a transcriptional program associated with Stat5- and TCR-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface MHC class II upregulation during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis led to the transfer of CD80 and CD86 costimulatory ligands from maturing cDCs to TR cells. In NOD mice, Fc.IL-2 mutein treatment promoted the suppression of cDCs in the inflamed pancreas and pancreatic lymph nodes resulting in T cell anergy. Thus, IL-2 mutein-expanded TR cells have enhanced functional properties and restrict cDC function, offering promise for targeted immunotherapy use in autoimmune disease.

2023-12-08 | GSE249186 | GEO

An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells

Project description:An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells

| PRJNA1049360 | ENA

An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells [RNA-seq]

Project description:An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells [RNA-seq]

| PRJNA1047623 | ENA

Selective activation and expansion of regulatory T cells using lipid encapsulated mRNA encoding a long-acting IL-2 mutein

Project description:Interleukin-2 (IL-2) is critical for regulatory T cell (Treg) function and homeostasis. At low doses, IL-2 can suppress immune pathologies by expanding Tregs that constitutively express the high affinity IL-2Rα subunit. However, even low doses IL-2, signaling through the IL2-Rβ/γ complex, may lead to the activation of proinflammatory, non-Treg T cells, so improving specificity toward Tregs may be desirable. Here we used messenger RNAs (mRNA) to encode a half-life-extended human IL-2 mutein (HSA-IL2m) with mutations promoting reliance on IL-2Rα. Our data show that IL-2 mutein subcutaneous delivery in lipid-encapsulated mRNA nanoparticles selectively activates and expands Tregs in mice and non-human primates, as well as reduces disease severity in mouse models of acute graft versus host disease and experimental autoimmune encephalomyelitis. Single cell RNA sequencing of murine splenic CD4+ T cells identifies multiple Treg states with distinct response dynamics following IL-2 mutein treatment. Our results thus demonstrate the potential of mRNA-encoded HSA-IL2m immunotherapy to treat autoimmune diseases.

2022-04-07 | GSE200142 | GEO

An Engineered IL-15 Cytokine Mutein Fused to an Anti-PD-1 Antibody Improves Intratumoral T Cell Function and Anti-tumor Immunity

Project description:The anti-PD-1 antibody-IL-15 cytokine fusion approach was developed to optimally activate intra-tumoral CD8+ T cells. We engineered a fusion protein of a single, potency-reduced, IL-15 mutein and an anti-PD-1 antibody (αPD1-IL15m). This immunocytokine is designed to deliver PD-1-mediated avidity-driven IL-2/15 receptor stimulation preferentially to PD-1-positive tumor-infiltrating lymphocytes (TILs) while reducing the natural preference of IL-15 for circulating peripheral NK or T cells.

2021-07-13 | GSE160579 | GEO

An Engineered IL-15 Cytokine Mutein Fused to an Anti-PD1 Antibody Improves Intratumoral T Cell Function and Anti-tumor Immunity (human)

Project description:Background: Cancer Immunotherapy with cytokines has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune activation. Here, we addressed these challenges by engineering a fusion protein of a single, potency-reduced, IL-15 mutein and an anti-PD1 antibody (αPD1-IL15m). This immunocytokine is designed to deliver PD1-mediated avidity-driven IL-2/15 receptor stimulation preferentially to PD1-positive tumor-infiltrating lymphocytes (TILs) while reducing the natural preference of IL-15 for circulating peripheral NK or T cell Methods: We isolated human lymphocytes from resected hepatocellular carcinoma tissue and cultured these tumor-infiltrating lymphocytes (TILs) in vitro in the presence or absence of an PD1-targeted IL15 mutein, anti-PD1 antibody or IL-15 agonist. After 9 days, CD4+ TILs and CD8+ TILs were sorted by FACS and RNA of 3,000 to 150,000 cells was isolated. Results: The PD1-IL15 fusion cytokine enhanced pro-survival, proliferation and activation pathways in tumor-infiltrating CD4+ and CD8+ cells compared to untreated controls as well as to the combined treatment of single agents (anti-PD1 antibody and IL-15 agonist)

2021-05-25 | GSE157893 | GEO

An IL-2 mutein increases IL-10 and CTLA-4-dependent suppression of dendritic cells by regulatory T cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-08 | GSE249482 | GEO

IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein (scRNA-Seq)

Project description:Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin (IL)-2, a critical cytokine in T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation and anti-tumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Ra with higher affinity, triggers STAT5 activation and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Finally, we find that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.

2022-12-02 | GSE213440 | GEO

IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein (RNA-Seq)

2022-12-02 | GSE213439 | GEO