Polyamine: A metabolic compass for T helper cell fate direction
TL;DR: Puleston et al. as mentioned in this paper used metabolomic, computational, and genetic approaches to uncover that polyamine metabolism directs T helper cell lineage choices, epigenetic state, and pathogenic potential in inflammation.
About: This article is published in Cell.The article was published on 2021-08-05. It has received 6 citations till now. The article focuses on the topics: Cell Fate Control & T helper cell.
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01 Nov 2015
TL;DR: In this article, the authors used single-cell RNA-seq to identify CD5L/AIM as a regulator expressed in non-pathogenic, but not in pathogenic Th17 cells.
Abstract: Summary Th17 cells play a critical role in host defense against extracellular pathogens and tissue homeostasis but can induce autoimmunity. The mechanisms implicated in balancing "pathogenic" and "non-pathogenic" Th17 cell states remain largely unknown. We used single-cell RNA-seq to identify CD5L/AIM as a regulator expressed in non-pathogenic, but not in pathogenic Th17 cells. Although CD5L does not affect Th17 differentiation, it is a functional switch that regulates the pathogenicity of Th17 cells. Loss of CD5L converts non-pathogenic Th17 cells into pathogenic cells that induce autoimmunity. CD5L mediates this effect by modulating the intracellular lipidome, altering fatty acid composition and restricting cholesterol biosynthesis and, thus, ligand availability for Rorγt, the master transcription factor of Th17 cells. Our study identifies CD5L as a critical regulator of the Th17 cell functional state and highlights the importance of lipid metabolism in balancing immune protection and disease induced by T cells.
229 citations
TL;DR: How rewiring of cellular metabolism determines the outcome of adaptive immunity in vivo is summarized, with a focus on how metabolites, nutrients, and driver genes in immunometabolism instruct cellular programming and immune responses during infection, inflammation, and cancer in mice and humans.
45 citations
TL;DR: In this paper , the authors delineate immunometabolic reprogramming as a critical hallmark of cancer by linking chronic inflammation and immunosuppression to cancer growth and metastasis.
Abstract: Molecular carcinogenesis is a multistep process that involves acquired abnormalities in key biological processes. The complexity of cancer pathogenesis is best illustrated in the six hallmarks of the cancer: (1) the development of self-sufficient growth signals, (2) the emergence of clones that are resistant to apoptosis, (3) resistance to the antigrowth signals, (4) neo-angiogenesis, (5) the invasion of normal tissue or spread to the distant organs, and (6) limitless replicative potential. It also appears that non-resolving inflammation leads to the dysregulation of immune cell metabolism and subsequent cancer progression. The present article delineates immunometabolic reprogramming as a critical hallmark of cancer by linking chronic inflammation and immunosuppression to cancer growth and metastasis. We propose that targeting tumor immunometabolic reprogramming will lead to the design of novel immunotherapeutic approaches to cancer.
2 citations
TL;DR: Two novel SAT1 LOF variants were identified, showed the ability of the frameshift variant to confer murine lupus, highlighted the pathogenic role of dysregulated polyamine catabolism and identified SAT1LOF variants as new monogenic causes for SLE.
Abstract: Objectives Families that contain multiple siblings affected with childhood onset of systemic lupus erythematosus (SLE) likely have strong genetic predispositions. We performed whole exome sequencing (WES) to identify familial rare risk variants and to assess their effects in lupus. Methods Sanger sequencing validated the two ultra-rare, predicted pathogenic risk variants discovered by WES and identified additional variants in 562 additional patients with SLE. Effects of a splice site variant and a frameshift variant were assessed using a Minigene assay and CRISPR/Cas9-mediated knock-in (KI) mice, respectively. Results The two familial ultra-rare, predicted loss-of-function (LOF) SAT1 variants exhibited X-linked recessive Mendelian inheritance in two unrelated African–American families. Each LOF variant was transmitted from the heterozygous unaffected mother to her two sons with childhood-onset SLE. The p.Asp40Tyr variant affected a splice donor site causing deleterious transcripts. The young hemizygous male and homozygous female Sat1 p.Glu92Leufs*6 KI mice spontaneously developed splenomegaly, enlarged glomeruli with leucocyte infiltration, proteinuria and elevated expression of type I interferon-inducible genes. SAT1 is highly expressed in neutrophils and encodes spermidine/spermine-N1-acetyltransferase 1 (SSAT1), a rate-limiting enzyme in polyamine catabolism. Young male KI mice exhibited neutrophil defects and decreased proportions of Foxp3 +CD4+ T-cell subsets. Circulating neutrophil counts and proportions of Foxp3 +CD4+ T cells correlated with decreased plasma levels of spermine in treatment-naive, incipient SLE patients. Conclusions We identified two novel SAT1 LOF variants, showed the ability of the frameshift variant to confer murine lupus, highlighted the pathogenic role of dysregulated polyamine catabolism and identified SAT1 LOF variants as new monogenic causes for SLE.
1 citations
TL;DR: The authors showed that miR-542-5p expression positively correlated with the levels of polyamine synthetases in peripheral blood mononuclear cells of patients with SLE as well as disease severity.
1 citations
References
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TL;DR: Metabolic tracer analysis revealed a Myc-dependent metabolic pathway linking glutaminolysis to the biosynthesis of polyamines, which may represent a general mechanism for metabolic reprogramming under patho-physiological conditions.
1,632 citations
TL;DR: New insights into molecular mechanisms that link the dysregulation of polyamine metabolism with carcinogenesis and strategies for targeting this pathway for cancer therapy are discussed.
Abstract: Advances in our understanding of the metabolism and molecular functions of polyamines and their alterations in cancer have led to resurgence in the interest of targeting polyamine metabolism as an anticancer strategy. Increasing knowledge of the interplay between polyamine metabolism and other cancer-driving pathways, including the PTEN–PI3K–mTOR complex 1 (mTORC1), WNT signalling and RAS pathways, suggests potential combination therapies that will have considerable clinical promise. Additionally, an expanding number of promising clinical trials with agents targeting polyamines for both therapy and prevention are ongoing. New insights into molecular mechanisms linking dysregulated polyamine catabolism and carcinogenesis suggest additional strategies that can be used for cancer prevention in at-risk individuals. In addition, polyamine blocking therapy, a strategy that combines the inhibition of polyamine biosynthesis with the simultaneous blockade of polyamine transport, can be more effective than therapies based on polyamine depletion alone and may involve an antitumour immune response. These findings open up new avenues of research into exploiting aberrant polyamine metabolism for anticancer therapy. This Review discusses new insights into molecular mechanisms that link the dysregulation of polyamine metabolism with carcinogenesis and strategies for targeting this pathway for cancer therapy.
398 citations
TL;DR: It is proposed that immunological cues and nutrients license and tune metabolic programmes and signalling networks that communicate in a bidirectional manner to promote quiescence exit and how cell-extrinsic factors, such as nutrients and regulatory T cells, directly and indirectly balance quiescent and activation programmes in conventional T cells.
Abstract: Naive T cells are actively maintained in a quiescent state that promotes their survival and persistence. On antigen stimulation, T cells exit quiescence to initiate clonal expansion and effector differentiation. Initial studies focused on the immune receptors and transcriptional regulators involved in T cell quiescence and activation, but recent findings highlight cell metabolism as a crucial regulator of these processes. Here we summarize these intrinsic metabolic programmes and also describe how cell-extrinsic factors, such as nutrients and regulatory T cells, directly and indirectly balance quiescence and activation programmes in conventional T cells. We propose that immunological cues and nutrients license and tune metabolic programmes and signalling networks that communicate in a bidirectional manner to promote quiescence exit. Understanding the programmes that regulate T cell quiescence will be key for developing novel approaches to modulate protective and pathological T cell responses in human diseases. Emerging studies highlight cell metabolism as a crucial regulator of T cell quiescence and activation. This Review describes how immunological cues and nutrients fine-tune metabolic programmes and signalling networks that together promote T cell quiescence exit.
338 citations
TL;DR: This study identifies CD5L as a critical regulator of the Th17 cell functional state and highlights the importance of lipid metabolism in balancing immune protection and disease induced by T cells.
279 citations
01 Nov 2015
TL;DR: In this article, the authors used single-cell RNA-seq to identify CD5L/AIM as a regulator expressed in non-pathogenic, but not in pathogenic Th17 cells.
Abstract: Summary Th17 cells play a critical role in host defense against extracellular pathogens and tissue homeostasis but can induce autoimmunity. The mechanisms implicated in balancing "pathogenic" and "non-pathogenic" Th17 cell states remain largely unknown. We used single-cell RNA-seq to identify CD5L/AIM as a regulator expressed in non-pathogenic, but not in pathogenic Th17 cells. Although CD5L does not affect Th17 differentiation, it is a functional switch that regulates the pathogenicity of Th17 cells. Loss of CD5L converts non-pathogenic Th17 cells into pathogenic cells that induce autoimmunity. CD5L mediates this effect by modulating the intracellular lipidome, altering fatty acid composition and restricting cholesterol biosynthesis and, thus, ligand availability for Rorγt, the master transcription factor of Th17 cells. Our study identifies CD5L as a critical regulator of the Th17 cell functional state and highlights the importance of lipid metabolism in balancing immune protection and disease induced by T cells.
229 citations