bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2021–04–18
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging.
  2. Interferon regulatory factor 4 controls effector functions of CD8+ memory T cells.
  3. E2A-regulated epigenetic landscape promotes memory CD8 T cell differentiation.
  4. Immunometabolism the CyTOF way.
  5. Epigenetic modulation of immune synaptic-cytoskeletal networks potentiates γδ T cell-mediated cytotoxicity in lung cancer.
  6. Effect of Lipids and Lipoproteins on Hematopoietic Cell Metabolism and Commitment in Atherosclerosis.
  7. Age-Related Dynamics of Lung-Resident Memory CD8+ T Cells in the Age of COVID-19.
  8. Glucose makes Treg lose their temper.
  9. Epigenetic alteration contributes to the transcriptional reprogramming in T-cell prolymphocytic leukemia.
  10. UTX promotes CD8+ T cell-mediated antiviral defenses but reduces T cell durability.
  11. Identification of VIMP as a gene inhibiting cytokine production in human CD4+ effector T cells.
  12. Selenoprotein W ensures physiological bone remodeling by preventing hyperactivity of osteoclasts.
  1. Cell Stem Cell. 2021 Apr 07. pii: S1934-5909(21)00123-5. [Epub ahead of print]
    Decline in IGF1 in the bone marrow microenvironment initiates hematopoietic stem cell aging.
    Kira Young, Elizabeth Eudy, Rebecca Bell, Matthew A Loberg, Tim Stearns, Devyani Sharma, Lars Velten, Simon Haas, Marie-Dominique Filippi, Jennifer J Trowbridge.
      Decline in hematopoietic stem cell (HSC) function with age underlies limited health span of our blood and immune systems. In order to preserve health into older age, it is necessary to understand the nature and timing of initiating events that cause HSC aging. By performing a cross-sectional study in mice, we discover that hallmarks of aging in HSCs and hematopoiesis begin to accumulate by middle age and that the bone marrow (BM) microenvironment at middle age induces and is indispensable for hematopoietic aging. Using unbiased approaches, we find that decreased levels of the longevity-associated molecule IGF1 in the local middle-aged BM microenvironment are a factor causing HSC aging. Direct stimulation of middle-aged HSCs with IGF1 rescues molecular and functional hallmarks of aging, including restored mitochondrial activity. Thus, although decline in IGF1 supports longevity, our work indicates that this also compromises HSC function and limits hematopoietic health span.
    Keywords:  IGF1; aging; healthspan; hematopoiesis; hematopoietic stem cell; lineage bias; metabolism; microenvironment; middle age; niche
    DOI:  https://doi.org/10.1016/j.stem.2021.03.017
  2. Proc Natl Acad Sci U S A. 2021 Apr 20. pii: e2014553118. [Epub ahead of print]118(16):
    Interferon regulatory factor 4 controls effector functions of CD8+ memory T cells.
    Aenne Harberts, Constantin Schmidt, Joanna Schmid, Daniel Reimers, Friedrich Koch-Nolte, Hans-Willi Mittrücker, Friederike Raczkowski.
      The transcription factor IRF4 is required for CD8+ T cell activation, proliferation, and differentiation to effector cells and thus is essential for robust CD8+ T cell responses. The function of IRF4 in memory CD8+ T cells yet needs to be explored. To investigate the role of IRF4 for maintaining differentiation state and survival of CD8+ memory T cells, we used a mouse model with tamoxifen-inducible Irf4 knockout to preclude effects due to inefficient memory cell differentiation in absence of IRF4. We infected mice with ovalbumin-recombinant listeria and induced Irf4 knockout after clearance of the pathogen. Loss of IRF4 resulted in phenotypical changes of CD8+ memory T cells but did not cause a reduction of the total memory T cell population. However, upon reencounter of the pathogen, CD8+ memory T cells showed impaired expansion and acquisition of effector functions. When compared to CD8+ effector memory T cells, CD8+ tissue-resident memory T cells (TRM cells) expressed higher IRF4 levels. Mice with constitutive Irf4 knockout had diminished CD8+ TRM-cell populations, and tamoxifen-induced Irf4 deletion caused a reduction of this cell population. In conclusion, our results demonstrate that IRF4 is required for effective reactivation but not for general survival of CD8+ memory T cells. Formation and maintenance of CD8+ TRM cells, in contrast, appear to depend on IRF4.
    Keywords:  CD8+ T cells; Listeria monocytogenes; interferon regulatory factor 4; memory T cells
    DOI:  https://doi.org/10.1073/pnas.2014553118
  3. Proc Natl Acad Sci U S A. 2021 Apr 20. pii: e2013452118. [Epub ahead of print]118(16):
    E2A-regulated epigenetic landscape promotes memory CD8 T cell differentiation.
    David M Schauder, Jian Shen, Yao Chen, Moujtaba Y Kasmani, Matthew R Kudek, Robert Burns, Weiguo Cui.
      During an acute viral infection, CD8 T cells encounter a myriad of antigenic and inflammatory signals of variable strength, which sets off individual T cells on their own differentiation trajectories. However, the developmental path for each of these cells will ultimately lead to one of only two potential outcomes after clearance of the infection-death or survival and development into memory CD8 T cells. How this cell fate decision is made remains incompletely understood. In this study, we explore the transcriptional changes during effector and memory CD8 T cell differentiation at the single-cell level. Using single-cell, transcriptome-derived gene regulatory network analysis, we identified two main groups of regulons that govern this differentiation process. These regulons function in concert with changes in the enhancer landscape to confer the establishment of the regulatory modules underlying the cell fate decision of CD8 T cells. Furthermore, we found that memory precursor effector cells maintain chromatin accessibility at enhancers for key memory-related genes and that these enhancers are highly enriched for E2A binding sites. Finally, we show that E2A directly regulates accessibility of enhancers of many memory-related genes and that its overexpression increases the frequency of memory precursor effector cells and accelerates memory cell formation while decreasing the frequency of short-lived effector cells. Overall, our results suggest that effector and memory CD8 T cell differentiation is largely regulated by two transcriptional circuits, with E2A serving as an important epigenetic regulator of the memory circuit.
    Keywords:  CD8 T cell; LCMV; T cell memory; epigenetics; scRNA-seq
    DOI:  https://doi.org/10.1073/pnas.2013452118
  4. Immunity. 2021 Apr 13. pii: S1074-7613(21)00131-X. [Epub ahead of print]54(4): 610-613
    Immunometabolism the CyTOF way.
    Liujia Qian, Tiannan Guo.
      In this issue of Immunity, Levine et al. report a CyTOF-based approach for the analyses of CD8+ T cells metabolic changes at the single-cell level. This approach identified a transition state early in T cell activation that is characterized by high glycolytic and oxidative activity, providing new insight into the metabolic changes that underlie the transition to effector and memory T cell fates.
    DOI:  https://doi.org/10.1016/j.immuni.2021.03.019
  5. Nat Commun. 2021 04 12. 12(1): 2163
    Epigenetic modulation of immune synaptic-cytoskeletal networks potentiates γδ T cell-mediated cytotoxicity in lung cancer.
    Rueyhung R Weng, Hsuan-Hsuan Lu, Chien-Ting Lin, Chia-Chi Fan, Rong-Shan Lin, Tai-Chung Huang, Shu-Yung Lin, Yi-Jhen Huang, Yi-Hsiu Juan, Yi-Chieh Wu, Zheng-Ci Hung, Chi Liu, Xuan-Hui Lin, Wan-Chen Hsieh, Tzu-Yuan Chiu, Jung-Chi Liao, Yen-Ling Chiu, Shih-Yu Chen, Chong-Jen Yu, Hsing-Chen Tsai.
      γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune system and can attack cancer cells in an MHC-unrestricted manner. Trials of adoptive γδ T cell transfer in solid tumors have had limited success. Here, we show that DNA methyltransferase inhibitors (DNMTis) upregulate surface molecules on cancer cells related to γδ T cell activation using quantitative surface proteomics. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded Vδ1-enriched γδ T cells. Mechanistically, DNMTi enhances immune synapse formation and mediates cytoskeletal reorganization via coordinated alterations of DNA methylation and chromatin accessibility. Genetic depletion of adhesion molecules or pharmacological inhibition of actin polymerization abolishes the potentiating effect of DNMTi. Clinically, the DNMTi-associated cytoskeleton signature stratifies lung cancer patients prognostically. These results support a combinatorial strategy of DNMTis and γδ T cell-based immunotherapy in lung cancer management.
    DOI:  https://doi.org/10.1038/s41467-021-22433-4
  6. Immunometabolism. 2021 Mar 29. 3(2): e210014
    Effect of Lipids and Lipoproteins on Hematopoietic Cell Metabolism and Commitment in Atherosclerosis.
    Andrea Baragetti, Fabrizia Bonacina, Alberico Luigi Catapano, Giuseppe Danilo Norata.
      Hematopoiesis is the process that leads to multiple leukocyte lineage generation within the bone marrow. This process is maintained throughout life thanks to a nonstochastic division of hematopoietic stem cells (HSCs), where during each division, one daughter cell retains pluripotency while the other differentiates into a restricted multipotent progenitor (MPP) that converts into mature, committed circulating cell. This process is tightly regulated at the level of cellular metabolism and the shift from anaerobic glycolysis, typical of quiescent HSC, to oxidative metabolism fosters HSCs proliferation and commitment. Systemic and local factors influencing metabolism alter HSCs balance under pathological conditions, with chronic metabolic and inflammatory diseases driving HSCs commitment toward activated blood immune cell subsets. This is the case of atherosclerosis, where impaired systemic lipid metabolism affects HSCs epigenetics that reflects into increased differentiation toward activated circulating subsets. Aim of this review is to discuss the impact of lipids and lipoproteins on HSCs pathophysiology, with a focus on the molecular mechanisms influencing cellular metabolism. A better understanding of these aspects will shed light on innovative strategies to target atherosclerosis-associated inflammation.
    Keywords:  atherosclerosis; cellular metabolism; cholesterol; hematopoiesis
    DOI:  https://doi.org/10.20900/immunometab20210014
  7. Front Immunol. 2021 ;12 636118
    Age-Related Dynamics of Lung-Resident Memory CD8+ T Cells in the Age of COVID-19.
    Nick P Goplen, In Su Cheon, Jie Sun.
      Following respiratory viral infections or local immunizations, lung resident-memory T cells (TRM) of the CD8 lineage provide protection against the same pathogen or related pathogens with cross-reactive T cell epitopes. Yet, it is now clear that, if homeostatic controls are lost following viral pneumonia, CD8 TRM cells can mediate pulmonary pathology. We recently showed that the aging process can result in loss of homeostatic controls on CD8 TRM cells in the respiratory tract. This may be germane to treatment modalities in both influenza and coronavirus disease 2019 (COVID-19) patients, particularly, the portion that present with symptoms linked to long-lasting lung dysfunction. Here, we review the developmental cues and functionalities of CD8 TRM cells in viral pneumonia models with a particular focus on their capacity to mediate heterogeneous responses of immunity and pathology depending on immune status.
    Keywords:  age; homeostasis; influenza; pathology; resident memory; viral pneumonia
    DOI:  https://doi.org/10.3389/fimmu.2021.636118
  8. Cancer Cell. 2021 Apr 12. pii: S1535-6108(21)00159-8. [Epub ahead of print]39(4): 460-462
    Glucose makes Treg lose their temper.
    Matteo Villa, David O'Sullivan, Erika L Pearce.
      Competition for glucose regulates the balance between cancer and immune responses. New findings published in Nature show that regulatory T cells (Treg) shape their metabolism to avoid glucose competition, thus maintaining their stability and sustaining tumor progression. This research suggests hijacking the "eating habits" of Treg could improve cancer therapy.
    DOI:  https://doi.org/10.1016/j.ccell.2021.03.001
  9. Sci Rep. 2021 Apr 15. 11(1): 8318
    Epigenetic alteration contributes to the transcriptional reprogramming in T-cell prolymphocytic leukemia.
    Shulan Tian, Henan Zhang, Pan Zhang, Michael Kalmbach, Jeong-Heon Lee, Tamas Ordog, Paul J Hampel, Timothy G Call, Thomas E Witzig, Neil E Kay, Eric W Klee, Susan L Slager, Huihuang Yan, Wei Ding.
      T cell prolymphocytic leukemia (T-PLL) is a rare disease with aggressive clinical course. Cytogenetic analysis, whole-exome and whole-genome sequencing have identified primary structural alterations in T-PLL, including inversion, translocation and copy number variation. Recurrent somatic mutations were also identified in genes encoding chromatin regulators and those in the JAK-STAT signaling pathway. Epigenetic alterations are the hallmark of many cancers. However, genome-wide epigenomic profiles have not been reported in T-PLL, limiting the mechanistic study of its carcinogenesis. We hypothesize epigenetic mechanisms also play a key role in T-PLL pathogenesis. To systematically test this hypothesis, we generated genome-wide maps of regulatory regions using H3K4me3 and H3K27ac ChIP-seq, as well as RNA-seq data in both T-PLL patients and healthy individuals. We found that genes down-regulated in T-PLL are mainly associated with defense response, immune system or adaptive immune response, while up-regulated genes are enriched in developmental process, as well as WNT signaling pathway with crucial roles in cell fate decision. In particular, our analysis revealed a global alteration of regulatory landscape in T-PLL, with differential peaks highly enriched for binding motifs of immune related transcription factors, supporting the epigenetic regulation of oncogenes and genes involved in DNA damage response and T-cell activation. Together, our work reveals a causal role of epigenetic dysregulation in T-PLL.
    DOI:  https://doi.org/10.1038/s41598-021-87890-9
  10. Cell Rep. 2021 Apr 13. pii: S2211-1247(21)00280-1. [Epub ahead of print]35(2): 108966
    UTX promotes CD8+ T cell-mediated antiviral defenses but reduces T cell durability.
    Joseph E Mitchell, Makayla M Lund, Josh Starmer, Kai Ge, Terry Magnuson, Karl B Shpargel, Jason K Whitmire.
      Persistent virus infections can cause pathogenesis that is debilitating or lethal. During these infections, virus-specific T cells fail to protect due to weakened antiviral activity or failure to persist. These outcomes are governed by histone modifications, although it is unknown which enzymes contribute to T cell loss or impaired function over time. In this study, we show that T cell receptor-stimulated CD8+ T cells increase their expression of UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome) to enhance gene expression. During chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, UTX binds to enhancers and transcription start sites of effector genes, allowing for improved cytotoxic T lymphocyte (CTL)-mediated protection, independent of its trimethylation of histone 3 lysine 27 (H3K27me3) demethylase activity. UTX also limits the frequency and durability of virus-specific CD8+ T cells, which correspond to increased expression of inhibitory receptors. Thus, UTX guides gene expression patterns in CD8+ T cells, advancing early antiviral defenses while reducing the longevity of CD8+ T cell responses.
    Keywords:  CD8(+) T cell function; LCMV; antiviral defense; epigenetics; histone demethylation; persistent infection
    DOI:  https://doi.org/10.1016/j.celrep.2021.108966
  11. iScience. 2021 Apr 23. 24(4): 102289
    Identification of VIMP as a gene inhibiting cytokine production in human CD4+ effector T cells.
    Christophe M Capelle, Ni Zeng, Egle Danileviciute, Sabrina Freitas Rodrigues, Markus Ollert, Rudi Balling, Feng Q He.
      Many players regulating the CD4+ T cell-mediated inflammatory response have already been identified. However, the critical nodes that constitute the regulatory and signaling networks underlying CD4 T cell responses are still missing. Using a correlation-network-guided approach, here we identified VIMP (VCP-interacting membrane protein), one of the 25 genes encoding selenoproteins in humans, as a gene regulating the effector functions of human CD4 T cells, especially production of several cytokines including IL2 and CSF2. We identified VIMP as an endogenous inhibitor of cytokine production in CD4 effector T cells via both the E2F5 transcription regulatory pathway and the Ca2+/NFATC2 signaling pathway. Our work not only indicates that VIMP might be a promising therapeutic target for various inflammation-associated diseases but also shows that our network-guided approach can significantly aid in predicting new functions of the genes of interest.
    Keywords:  Cell Biology; Immunology; Systems Biology
    DOI:  https://doi.org/10.1016/j.isci.2021.102289
  12. Nat Commun. 2021 04 15. 12(1): 2258
    Selenoprotein W ensures physiological bone remodeling by preventing hyperactivity of osteoclasts.
    Hyunsoo Kim, Kyunghee Lee, Jin Man Kim, Mi Yeong Kim, Jae-Ryong Kim, Han-Woong Lee, Youn Wook Chung, Hong-In Shin, Taesoo Kim, Eui-Soon Park, Jaerang Rho, Seoung Hoon Lee, Nacksung Kim, Soo Young Lee, Yongwon Choi, Daewon Jeong.
      Selenoproteins containing selenium in the form of selenocysteine are critical for bone remodeling. However, their underlying mechanism of action is not fully understood. Herein, we report the identification of selenoprotein W (SELENOW) through large-scale mRNA profiling of receptor activator of nuclear factor (NF)-κΒ ligand (RANKL)-induced osteoclast differentiation, as a protein that is downregulated via RANKL/RANK/tumour necrosis factor receptor-associated factor 6/p38 signaling. RNA-sequencing analysis revealed that SELENOW regulates osteoclastogenic genes. SELENOW overexpression enhances osteoclastogenesis in vitro via nuclear translocation of NF-κB and nuclear factor of activated T-cells cytoplasmic 1 mediated by 14-3-3γ, whereas its deficiency suppresses osteoclast formation. SELENOW-deficient and SELENOW-overexpressing mice exhibit high bone mass phenotype and osteoporosis, respectively. Ectopic SELENOW expression stimulates cell-cell fusion critical for osteoclast maturation as well as bone resorption. Thus, RANKL-dependent repression of SELENOW regulates osteoclast differentiation and blocks osteoporosis caused by overactive osteoclasts. These findings demonstrate a biological link between selenium and bone metabolism.
    DOI:  https://doi.org/10.1038/s41467-021-22565-7
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