bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2022‒08‒28
eight papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research
  1. CD4+ T cell metabolism, gut microbiota, and autoimmune diseases: implication in precision medicine of autoimmune diseases.
  2. Editorial: T cell metabolism in infection.
  3. miR-150 promotes progressive T cell differentiation via inhibiting FOXP1 and RC3H1.
  4. CD5 Suppresses IL-15-Induced Proliferation of Human Memory CD8+ T Cells by Inhibiting mTOR Pathways.
  5. The histone deacetylases Rpd3 and Hst1 antagonistically regulate de novo NAD+ metabolism in the budding yeast Saccharomyces cerevisiae.
  6. Zeb1 sustains hematopoietic stem cell functions by suppressing mitofusin-2-mediated mitochondrial fusion.
  7. BECN1F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner.
  8. Leaky mitochondria.
  1. Precis Clin Med. 2022 Sep;5(3): pbac018
    CD4+ T cell metabolism, gut microbiota, and autoimmune diseases: implication in precision medicine of autoimmune diseases.
    Wenjing Yang, Tianming Yu, Yingzi Cong.
      CD4+ T cells are critical to the development of autoimmune disorders. Glucose, fatty acids, and glutamine metabolisms are the primary metabolic pathways in immune cells, including CD4+ T cells. The distinct metabolic programs in CD4+ T cell subsets are recognized to reflect the bioenergetic requirements, which are compatible with their functional demands. Gut microbiota affects T cell responses by providing a series of antigens and metabolites. Accumulating data indicate that CD4+ T cell metabolic pathways underlie aberrant T cell functions, thereby regulating the pathogenesis of autoimmune disorders, including inflammatory bowel diseases, systemic lupus erythematosus, and rheumatoid arthritis. Here, we summarize the current progress of CD4+ T cell metabolic programs, gut microbiota regulation of T cell metabolism, and T cell metabolic adaptions to autoimmune disorders to shed light on potential metabolic therapeutics for autoimmune diseases.
    Keywords:  autoimmune disorders; gut microbiota; immunometabolism; metabolic adaption
    DOI:  https://doi.org/10.1093/pcmedi/pbac018
  2. Front Immunol. 2022 ;13 956876
    Editorial: T cell metabolism in infection.
    Jin-Fu Xu, Ying-Zhou Xie, Duo-Jiao Wu.
      
    Keywords:  T cell; Tfh; infection; metabolism; therapeutics
    DOI:  https://doi.org/10.3389/fimmu.2022.956876
  3. Hum Immunol. 2022 Aug 20. pii: S0198-8859(22)00161-6. [Epub ahead of print]
    miR-150 promotes progressive T cell differentiation via inhibiting FOXP1 and RC3H1.
    Shengfang Xia, Jianqing Huang, Lijun Yan, Jiayi Han, Wenfeng Zhang, Hongwei Shao, Han Shen, Jinquan Wang, Jinquan Wang, Changli Tao, Dingding Wang, Fenglin Wu.
      T cells used in immune cell therapy, represented by T cell receptor therapy (TCR-T), are usually activated and proliferated in vitro and are induced to a terminally differentiated phenotype, with limited viability after transfusion back into the body. T cells exhibited a robust proliferative potential and in vivo viability in the early stages of progressive differentiation. In this study, we identified microRNAs that regulate T cell differentiation. After microRNA sequencing of the four subsets: Naïve T cells (TN), stem cell-like memory T cells (TSCM), central memory T cells (TCM）, and effector memory T cells (TEM), miR-150 was identified as the most highly expressed miRNA among the four subsets and was lowly expressed in the TSCM cells. We predicted the target genes of miR-150 miRNA and performed Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes analyses. We observed that the target genes of miR-150 were enriched in pathways associated with T-cell differentiation. FOXP1 and RC3H1 were identified as key target genes of miR-150 in the regulation of T-cell function. We examined the effects of miR-150 on the differentiation and function of healthy donor T-cells. We observed that miR-150 overexpression promoted T-cell differentiation to effector T-cells and effector memory T-cells, enhanced apoptosis, inhibited cell proliferation and increased secretion of pro-inflammatory cytokines such as IFN-γ and TNF-α. In addition, the expressions of early differentiation-related genes (ACTN1, CERS6, BCL2, and EOMES), advanced differentiation-related genes (KLRG1), and effector-function-related genes (PRF1 and GZMB) were significantly decreased after overexpression of miR-150. Collectively, our results suggested that miR-150 can promote progressive differentiation of T cells and the downmodulation of miR-150 expression while performing adoptive immunotherapy may inhibit T-cell differentiation and increase the proliferative potential of T cells.
    Keywords:  Progressive differentiation; T cell; microRNA
    DOI:  https://doi.org/10.1016/j.humimm.2022.08.006
  4. J Immunol. 2022 Aug 24. pii: ji2100854. [Epub ahead of print]
    CD5 Suppresses IL-15-Induced Proliferation of Human Memory CD8+ T Cells by Inhibiting mTOR Pathways.
    Young Joon Choi, Hoyoung Lee, Jong Hoon Kim, So-Young Kim, June-Young Koh, Moa Sa, Su-Hyung Park, Eui-Cheol Shin.
      IL-15 induces the proliferation of memory CD8+ T cells as well as NK cells. The expression of CD5 inversely correlates with the IL-15 responsiveness of human memory CD8+ T cells. However, whether CD5 directly regulates IL-15-induced proliferation of human memory CD8+ T cells is unknown. In the current study, we demonstrate that human memory CD8+ T cells in advanced stages of differentiation respond to IL-15 better than human memory CD8+ T cells in stages of less differentiation. We also found that the expression level of CD5 is the best correlate for IL-15 hyporesponsiveness among human memory CD8+ T cells. Importantly, we found that IL-15-induced proliferation of human memory CD8+ T cells is significantly enhanced by blocking CD5 with Abs or knocking down CD5 expression using small interfering RNA, indicating that CD5 directly suppresses the IL-15-induced proliferation of human memory CD8+ T cells. We also found that CD5 inhibits activation of the mTOR pathway, which is required for IL-15-induced proliferation of human memory CD8+ T cells. Taken together, the results indicate that CD5 is not just a correlative marker for IL-15 hyporesponsiveness, but it also directly suppresses IL-15-induced proliferation of human memory CD8+ T cells by inhibiting mTOR pathways.
    DOI:  https://doi.org/10.4049/jimmunol.2100854
  5. J Biol Chem. 2022 Aug 22. pii: S0021-9258(22)00853-5. [Epub ahead of print] 102410
    The histone deacetylases Rpd3 and Hst1 antagonistically regulate de novo NAD+ metabolism in the budding yeast Saccharomyces cerevisiae.
    Benjamin Groth, Chi-Chun Huang, Su-Ju Lin.
      NAD+ is a cellular redox cofactor involved in many essential processes. The regulation of NAD+ metabolism and the signaling networks reciprocally interacting with NAD+-producing metabolic pathways are not yet fully understood. The NAD+-dependent histone deacetylase (HDAC) Hst1 has been shown to inhibit de novo NAD+ synthesis by repressing biosynthesis of nicotinic acid (BNA) gene expression. Here, we alternatively identify HDAC Rpd3 as a positive regulator of de novo NAD+ metabolism in the budding yeast Saccharomyces cerevisiae. We reveal that deletion of RPD3 causes marked decreases in the production of de novo pathway metabolites, in direct contrast to deletion of HST1. We determined the BNA expression profiles of rpd3Δ and hst1Δ cells to be similarly opposed, suggesting the two HDACs may regulate the BNA genes in an antagonistic fashion. Our ChIP analysis revealed Rpd3 and Hst1 mutually influence each other's binding distribution at the BNA2 promoter. We demonstrate Hst1 to be the main deacetylase active at the BNA2 promoter, with hst1Δ cells displaying increased acetylation of the N-terminal tail lysine residues of histone H4, H4K5 and H4K12. Conversely, we show that deletion of RPD3 reduces the acetylation of these residues in a Hst1-dependent manner. This suggests Rpd3 may function to oppose spreading of Hst1-dependent heterochromatin and represents a unique form of antagonism between HDACs in regulating gene expression. Moreover, we found that Rpd3 and Hst1 also co-regulate additional targets involved in other branches of NAD+ metabolism. These findings help elucidate the complex interconnections involved in effecting the regulation of NAD+ metabolism.
    Keywords:  NAD(+) biosynthesis; cell metabolism; gene regulation; histone deacetylase; metabolic regulation; yeast genetics; yeast metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2022.102410
  6. Cell Death Dis. 2022 Aug 25. 13(8): 735
    Zeb1 sustains hematopoietic stem cell functions by suppressing mitofusin-2-mediated mitochondrial fusion.
    Kai Zhang, Huifang Zhao, Yaru Sheng, Xinyu Chen, Penghui Xu, Jinming Wang, Zhongzhong Ji, Yuman He, Wei-Qiang Gao, Helen He Zhu.
      Metabolic status is essential in maintaining normal functions of hematopoietic stem cells (HSCs). However, how the dynamic of the mitochondrion, as a central organelle in metabolism, is molecularly regulated to orchestrate metabolism and HSC stemness remains to be elucidated. Here, we focus on the role of Zeb1, a well-characterized epithelial-to-mesenchymal transition (EMT) inducer which has been demonstrated to confer stem-cell-like characteristics in multiple cancer types in stemness regulation of HSCs. Using a Zeb1-tdTomato reporter mouse model, we find that Zeb1+Lin-Sca-1+c-Kit+ cells (Zeb1+-LSKs) represent a subset of functional long-term HSCs. Zeb1+LSKs exhibit a reduced reactive oxygen species (ROS) level, low mitochondrial mass, low mitochondrial membrane potential (MMP), and particularly small, round fragmented mitochondria. Of note, ectopic expression of Zeb1 leads to a fragmented mitochondrial morphology with a low mitochondrial metabolic status in EML cells. In addition, Zeb1-knockout (Zeb1-KO) LSKs from fetal liver display an exhausted stem-cell activity. Zeb1 deficiency results in elongated and tubulated mitochondria with increased mitochondrial mass, elevated MMP, and higher ROS production. Mechanistically, Zeb1 acts as a transcriptional suppressor on the key mitochondrial-fusion protein Mitofusin-2 (encoded by Mfn2). We highlight an important role of Zeb1 in the regulation of mitochondrial morphology in HSC and the metabolic control of HSC stemness by repressing Mfn2-mediated mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41419-022-05194-w
  7. Autophagy. 2022 Aug 21. 1-9
    BECN1F121A mutation increases autophagic flux in aged mice and improves aging phenotypes in an organ-dependent manner.
    Salwa Sebti, Zhongju Zou, Michael U Shiloh.
      Macroautophagy/autophagy is necessary for lifespan extension in multiple model organisms and autophagy dysfunction impacts age-related phenotypes and diseases. Introduction of an F121A mutation into the essential autophagy protein BECN1 constitutively increases basal autophagy in young mice and reduces cardiac and renal age-related changes in longer lived Becn1F121A mutant mice. However, both autophagic and lysosomal activities decline with age. Thus, whether autophagic flux is maintained during aging and whether it is enhanced in Becn1F121A mice is unknown. Here, we demonstrate that old wild-type mice maintained functional autophagic flux in heart, kidney and skeletal muscle but not liver, and old Becn1F121A mice had increased autophagic flux in those same organs compared to wild type. In parallel, Becn1F121A mice were not protected against age-associated hepatic phenotypes but demonstrated reduced skeletal muscle fiber atrophy. These findings identify an organ-specific role for the ability of autophagy to impact organ aging phenotypes.
    Keywords:  Aging; BECN1; autophagic flux; liver; mouse; skeletal muscle
    DOI:  https://doi.org/10.1080/15548627.2022.2111852
  8. Nat Immunol. 2022 Aug 23.
    Leaky mitochondria.
    Nick Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-022-01305-z
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