bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–12–10
twenty-one papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function.
  2. The mitochondrial fission protein DRP1 influences memory CD8+ T cell formation and function.
  3. Fructose sweetens the adipocyte-T cell alliance against tumors.
  4. Checkmate: Metabolic flexibility with a STING in its tail.
  5. Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.
  6. Deletion of the protein tyrosine phosphatase PTPN22 for adoptive T cell therapy facilitates CTL effector function but promotes T cell exhaustion.
  7. Redox and detox: Malate shuttle metabolism keeps exhausted T cells fit.
  8. Aging gene signature of memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.
  9. Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity.
  10. Targeting the epigenome to reinvigorate T cells for cancer immunotherapy.
  11. Vitamin B12 boosts cellular reprogramming.
  12. Aging and the Emerging Role of Cellular Senescence in Osteoarthritis.
  13. Methionine availability influences essential H3K36me3 dynamics during cell differentiation.
  14. Soluble CTLA-4 attenuates T-cell activation and modulates anti-tumour immunity.
  15. Loss of cardiac PFKFB2 drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart.
  16. Aging and Inflammation.
  17. T cell migration requires ion and water influx to regulate actin polymerization.
  18. A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation.
  19. Isoleucine dietary restriction boosts healthspan and longevity in mice.
  20. Tox induces T cell IL-10 production in a BATF-dependent manner.
  21. IL-15-dependent immune crosstalk between natural killer cells and dendritic cells in HIV-1 elite controllers.
  1. Cell Rep. 2023 Dec 01. pii: S2211-1247(23)01530-9. [Epub ahead of print]42(12): 113518
    De novo NAD+ synthesis contributes to CD8+ T cell metabolic fitness and antitumor function.
    Jie Wan, Cheng Cheng, Jiajia Hu, Haiyan Huang, Qiaoqiao Han, Zuliang Jie, Qiang Zou, Jian-Hong Shi, Xiaoyan Yu.
      The dysfunction and clonal constriction of tumor-infiltrating CD8+ T cells are accompanied by alterations in cellular metabolism; however, how the cell-intrinsic metabolic pathway specifies intratumoral CD8+ T cell features remains elusive. Here, we show that cell-autonomous generation of nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway (KP) contributes to the maintenance of intratumoral CD8+ T cell metabolic and functional fitness. De novo NAD+ synthesis is involved in CD8+ T cell metabolism and antitumor function. KP-derived NAD+ promotes PTEN deacetylation, thereby facilitating PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, impaired cell-autonomous NAD+ synthesis limits CD8+ T cell responses in human colorectal cancer samples. Our results reveal that KP-derived NAD+ regulates the CD8+ T cell metabolic and functional state by restricting PTEN activity and suggest that modulation of de novo NAD+ synthesis could restore CD8+ T cell metabolic fitness and antitumor function.
    Keywords:  CP: Cancer; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.113518
  2. J Leukoc Biol. 2023 Dec 06. pii: qiad155. [Epub ahead of print]
    The mitochondrial fission protein DRP1 influences memory CD8+ T cell formation and function.
    Marissa G Stevens, Frank M Mason, Timothy N J Bullock.
      Pharmacological methods for promoting mitochondrial elongation suggest that effector T cells can be altered to support a memory T cell-like metabolic state. Such mitochondrial elongation approaches may enhance the development of immunological memory. Therefore, we hypothesized that deletion of the mitochondrial fission protein, DRP1, would lead to mitochondrial elongation and generate a large memory T cell population, an approach that could be exploited to enhance vaccination protocols. We find that, as expected, while deletion of DRP1 from T cells in dLckCre x Drp1flfl does compromise the magnitude and functionality of primary effector CD8+ T cells, a disproportionately large pool of memory CD8+ T cells does form. In contrast to primary effector CD8+ T cells, DRP1-deficient memory dLckCre x Drp1flfl CD8+ T cells mount a secondary response comparable to control memory T cells with respect to kinetics, magnitude, and effector capabilities. Interestingly, the relative propensity to form memory cells in the absence of DRP1 was neither associated with differentiation toward more memory precursor CD8+ T cells nor decreased cellular death of effector T cells. Instead, the tendency to form memory CD8+ T cells in the absence of DRP1 is associated with decreased TCR expression. Remarkably, in a competitive environment with DRP1-replete CD8+ T cells, the absence of DRP1 from CD8+ T cells compromised the generation of primary, memory and secondary responses, indicating that approaches targeting DRP1 need to be carefully tailored.
    Keywords:  CD8+ T cell; Cell Death; Cytokine; Differentiation; Memory T cell; Metabolism; Mitochondria; T cell receptor
    DOI:  https://doi.org/10.1093/jleuko/qiad155
  3. Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00415-1. [Epub ahead of print]35(12): 2093-2094
    Fructose sweetens the adipocyte-T cell alliance against tumors.
    Peipei Zhou, Hongbo Chi.
      Dietary fructose is implicated in tumorigenesis, but whether dietary fructose regulates antitumor immunity remains elusive. In this issue of Cell Metabolism, Zhang et al. show that dietary fructose promotes adipocyte-derived leptin production, which attenuates terminal exhaustion programming and boosts the effector function of CD8+ T cells for improved tumor control.
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.004
  4. Sci Adv. 2023 Dec 08. 9(49): eadm6816
    Checkmate: Metabolic flexibility with a STING in its tail.
    Roddy S O'Connor.
      Inhibiting a key metabolic enzyme, ACLY, in cancer cells impacts T cell function in immunotherapy-resistant tumors and may offer a target for therapeutic treatment.
    DOI:  https://doi.org/10.1126/sciadv.adm6816
  5. Sci Adv. 2023 Dec 08. 9(49): eadf9522
    Mitochondrial metabolic flexibility is critical for CD8+ T cell antitumor immunity.
    Chao Chen, Hong Zheng, Edwin M Horwitz, Satomi Ando, Koichi Araki, Peng Zhao, Zhiguo Li, Mandy L Ford, Rafi Ahmed, Cheng-Kui Qu.
      Mitochondria use different substrates for energy production and intermediatory metabolism according to the availability of nutrients and oxygen levels. The role of mitochondrial metabolic flexibility for CD8+ T cell immune response is poorly understood. Here, we report that the deletion or pharmacological inhibition of protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) significantly decreased CD8+ effector T cell development and clonal expansion. In addition, PTPMT1 deletion impaired stem-like CD8+ T cell maintenance and accelerated CD8+ T cell exhaustion/dysfunction, leading to aggravated tumor growth. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection-the utilization of pyruvate, a major mitochondrial substrate derived from glucose-was inhibited, whereas fatty acid utilization was enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress, DNA damage, and apoptosis in PTPMT1 knockout cells. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8+ T cell antitumor immunity.
    DOI:  https://doi.org/10.1126/sciadv.adf9522
  6. J Immunother Cancer. 2023 Dec 06. pii: e007614. [Epub ahead of print]11(12):
    Deletion of the protein tyrosine phosphatase PTPN22 for adoptive T cell therapy facilitates CTL effector function but promotes T cell exhaustion.
    Alexandra Rose Teagle, Patricia Castro-Sanchez, Rebecca J Brownlie, Nicola Logan, Simran S Kapoor, David Wright, Robert J Salmond, Rose Zamoyska.
       BACKGROUND: Adoptive cell therapy (ACT) is a promising strategy for treating cancer, yet it faces several challenges such as lack of long-term protection due to T cell exhaustion induced by chronic TCR stimulation in the tumor microenvironment. One benefit of ACT, however, is that it allows for cellular manipulations, such as deletion of the phosphotyrosine phosphatase non-receptor type 22 (PTPN22), which improves CD8+ T cell antitumor efficacy in ACT. We tested whether Ptpn22KO cytolytic T cells (CTLs) were also more effective than Ptpn22WT CTL in controlling tumors in scenarios that favor T cell exhaustion.
    METHODS: Tumor control by Ptpn22WT and Ptpn22KO CTL was assessed following adoptive transfer of low numbers of CTL to mice with subcutaneously implanted MC38 tumors. Tumor infiltrating lymphocytes were isolated for analysis of effector functions. An in vitro assay was established to compare CTL function in response to acute and chronic restimulation with antigen-pulsed tumor cells. The expression of effector and exhaustion-associated proteins by Ptpn22WT and Ptpn22KO T cells was followed over time in vitro and in vivo using the ID8 tumor model. Finally, the effect of PD-1 and TIM-3 blockade on Ptpn22KO CTL tumor control was assessed using monoclonal antibodies and CRISPR/Cas9-mediated knockout.
    RESULTS: Despite having improved effector function at the time of transfer, Ptpn22KO CTL became more exhausted than Ptpn22WT CTL, characterized by more rapid loss of effector functions, and earlier and higher expression of inhibitory receptors (IRs), particularly the terminal exhaustion marker TIM-3. TIM-3 expression, under the control of the transcription factor NFIL3, was induced by IL-2 signaling which was enhanced in Ptpn22KO cells. Antitumor responses of Ptpn22KO CTL were improved following PD-1 blockade in vivo, yet knockout or antibody-mediated blockade of TIM-3 did not improve but further impaired tumor control, indicating TIM-3 signaling itself did not drive the diminished function seen in Ptpn22KO CTL.
    CONCLUSIONS: This study questions whether TIM-3 plays a role as an IR and highlights that genetic manipulation of T cells for ACT needs to balance short-term augmented effector function against the risk of T cell exhaustion in order to achieve longer-term protection.
    Keywords:  CD8-Positive T-Lymphocytes; Cytotoxicity, Immunologic; Immune Checkpoint Inhibitors; Immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2023-007614
  7. Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00416-3. [Epub ahead of print]35(12): 2101-2103
    Redox and detox: Malate shuttle metabolism keeps exhausted T cells fit.
    Alok Kumar, Greg M Delgoffe.
      The malate shuttle is known to maintain the balance of NAD+/NADH between the cytosol and mitochondria. However, in Tex cells, it primarily detoxifies ammonia (via GOT1-mediated production of 2-KG in an atypical reaction) and provides longevity to chronic-infection-induced Tex cells against ammonia-induced cell death.
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.005
  8. Immun Ageing. 2023 Dec 02. 20(1): 71
    Aging gene signature of memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.
    Juan Joseph Young, Hong-Jai Park, Minhyung Kim, Jennefer Par-Young, Hugh Bartlett, Hye Sun Kim, Serhan Unlu, Lais Osmani, Min Sun Shin, Richard Bucala, Christopher H van Dyck, Heather Allore, Adam P Mecca, Sungyong You, Insoo Kang.
       BACKGROUND: Memory CD8+ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) and the presence of its gene signature (i.e., IL-7Rαlow aging genes) in peripheral blood of older adults without Alzheimer's disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8+ T cell expansion, mostly IL-7Rαlow cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rαlow aging gene signature, especially in relation to genes possibly associated with AD and disease severity.
    RESULTS: We identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rαlow aging genes (P < 0.001), suggesting the possible implication of IL-7Rαlow aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rαlow aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rαlow aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing.
    CONCLUSIONS: We report differential expression of "normal" aging genes associated with IL-7Rαlow EM CD8+ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8+ T cells, in AD.
    Keywords:  Adaptive immunity; Aging; Alzheimer’s disease; Senescence; T cell; Transcriptomics
    DOI:  https://doi.org/10.1186/s12979-023-00396-y
  9. Melanoma Res. 2023 Dec 04.
    Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity.
    Benjamin Switzer, Igor Puzanov, Shipra Gandhi, Elizabeth A Repasky.
      The intricate pathways of the sympathetic nervous system hold an inherently protective role in the setting of acute stress. This is achieved through dynamic immunomodulatory and neurobiological networks. However, excessive and chronic exposure to these stress-induced stimuli appears to cause physiologic dysfunction through several mechanisms that may impair psychosocial, neurologic, and immunologic health. Numerous preclinical observations have identified the beta-2 adrenergic receptor (β2-AR) subtype to possess the strongest impact on immune dysfunction in the setting of chronic stressful stimuli. This prolonged expression of β2-ARs appears to suppress immune surveillance and promote tumorigenesis within multiple cancer types. This occurs through several pathways, including (1) decreasing the frequency and function of CD8 + T-cells infiltrating the tumor microenvironment (TME) via inhibition of metabolic reprogramming during T cell activation, and (2) establishing an immunosuppressive profile within the TME including promotion of an exhausted T cell phenotype while simultaneously enhancing local and paracrine metastatic potential. The use of nonselective β-AR antagonists appears to reverse many chronic stress-induced tumorigenic pathways and may also provide an additive therapeutic benefit for various immune checkpoint modulating agents including commonly utilized immune checkpoint inhibitors. Here we review the translational and clinical observations highlighting the foundational hypotheses that chronic stress-induced β-AR signaling promotes a pro-tumoral immunophenotype and that blockade of these pathways may augment the therapeutic response of immune checkpoint inhibition within the scope of melanoma.
    DOI:  https://doi.org/10.1097/CMR.0000000000000943
  10. Mil Med Res. 2023 Dec 04. 10(1): 59
    Targeting the epigenome to reinvigorate T cells for cancer immunotherapy.
    Dian Xiong, Lu Zhang, Zhi-Jun Sun.
      Cancer immunotherapy using immune-checkpoint inhibitors (ICIs) has revolutionized the field of cancer treatment; however, ICI efficacy is constrained by progressive dysfunction of CD8+ tumor-infiltrating lymphocytes (TILs), which is termed T cell exhaustion. This process is driven by diverse extrinsic factors across heterogeneous tumor immune microenvironment (TIME). Simultaneously, tumorigenesis entails robust reshaping of the epigenetic landscape, potentially instigating T cell exhaustion. In this review, we summarize the epigenetic mechanisms governing tumor microenvironmental cues leading to T cell exhaustion, and discuss therapeutic potential of targeting epigenetic regulators for immunotherapies. Finally, we outline conceptual and technical advances in developing potential treatment paradigms involving immunostimulatory agents and epigenetic therapies.
    Keywords:  Cancer microbiome; Combination therapy; Epigenetic therapy; Immune checkpoint blockade; Immune macroenvironment; Immunometabolism; Spatial immune contexture; T cell exhaustion
    DOI:  https://doi.org/10.1186/s40779-023-00496-2
  11. Nat Aging. 2023 Dec 05.
    Vitamin B12 boosts cellular reprogramming.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-023-00546-3
  12. Osteoarthritis Cartilage. 2023 Dec 02. pii: S1063-4584(23)00997-4. [Epub ahead of print]
    Aging and the Emerging Role of Cellular Senescence in Osteoarthritis.
    Brian O Diekman, Richard F Loeser.
       OBJECTIVE: The correlation between age and incidence of osteoarthritis (OA) is well known but the causal mechanisms involved are not completely understood. This narrative review summarizes selected key findings from the past 30 years that have elucidated key aspects of the relationship between aging and OA.
    METHODS: The peer-reviewed English language literature was searched on PubMed using key words including senescence, aging, cartilage, and osteoarthritis, for original studies and reviews published from 1993-2023 with a major focus on more recent studies. Manuscripts most relevant to aging and OA that examined one or more of the hallmarks of aging were selected for further review.
    RESULTS: All proposed hallmarks of aging have been observed in articular cartilage and some have also been described in other joint tissues. Hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, disabled macroautophagy, chronic inflammation, and dysbiosis. There is evidence that these age-related changes contribute to the development of OA in part by promoting cellular senescence. Senescence may therefore serve as a downstream mediator that connects numerous aging hallmarks to OA, likely through the senescence-associated secretory phenotype (SASP) that is characterized by increased production of proinflammatory cytokines and matrix metalloproteinases.
    CONCLUSIONS: Progress over the past 30 years has provided the foundation for emerging therapies, such as senolytics and senomorphics, that hold promise for OA disease modification. Mechanistic studies utilizing physiologically-aged animals and cadaveric human joint tissues will be important for continued progress.
    Keywords:  Aging; Chondrocyte; cartilage; senescence
    DOI:  https://doi.org/10.1016/j.joca.2023.11.018
  13. bioRxiv. 2023 Nov 22. pii: 2023.11.22.568331. [Epub ahead of print]
    Methionine availability influences essential H3K36me3 dynamics during cell differentiation.
    Yudong Sun, Vijyendra Ramesh, Fangchao Wei, Jason W Locasale.
      Histone modifications are integral to epigenetics through their influence on gene expression and cellular status. While it's established that metabolism, including methionine metabolism, can impact histone methylation, the direct influence of methionine availability on crucial histone marks that determine the epigenomic process remains poorly understood. In this study, we demonstrate that methionine, through its metabolic product, S-adenosylmethionine (SAM), dynamically regulates H3K36me3, a cancer-associated histone modification known to influence cellular status, and myogenic differentiation of mouse myoblast cells. We further demonstrate that the methionine-dependent effects on differentiation are mediated in part through the histone methyltransferase SETD2. Methionine restriction leads to preferential decreases in H3K36me3 abundance and genome accessibility of genes involved in myogenic differentiation. Importantly, the effects of methionine restriction on differentiation and chromatin accessibility can be phenocopied by the deletion of Setd2. Collectively, this study demonstrates that methionine metabolism through its ability to be sensed by chromatin modifying enzymes can have a direct role in influencing cell fate determination.
    DOI:  https://doi.org/10.1101/2023.11.22.568331
  14. Mol Ther. 2023 Dec 05. pii: S1525-0016(23)00661-5. [Epub ahead of print]
    Soluble CTLA-4 attenuates T-cell activation and modulates anti-tumour immunity.
    Paul T Kennedy, Emma L Saulters, Andrew D Duckworth, Yeong Jer Lim, John F Woolley, Joseph R Slupsky, Mark S Cragg, Frank J Ward, Lekh N Dahal.
      CTLA-4 is a crucial immune checkpoint receptor involved in the maintenance of immune homeostasis, tolerance, and tumour control. Antibodies targeting CTLA-4 have been promising treatments for numerous cancers, but the mechanistic basis of their anti-tumoral immune boosting effects are poorly understood. Although the ctla4 gene also encodes an alternatively-spliced soluble variant (sCTLA-4), preclinical/clinical evaluation of anti-CTLA-4-based immunotherapies have not considered the contribution of this isoform. Here, we explore the functional properties of sCTLA-4 and evaluate the efficacy of isoform-specific anti-sCTLA-4 antibody targeting in murine cancer model. We show that expression of sCTLA-4 by tumour cells suppresses CD8+ T-cells in vitro, and accelerates growth and experimental metastasis of murine tumours in vivo. These effects were accompanied by modification of the immune infiltrate, notably restraining CD8+ T-cells in a non-cytotoxic state. sCTLA-4 blockade with isoform-specific antibody reversed this restraint, enhancing intratumoural CD8+ T-cell activation and cytolytic potential, correlating with therapeutic efficacy and tumour control. This previously unappreciated role of sCTLA-4 suggests that better understanding of the biology and function of multi-gene products of immune checkpoint receptors needs to be fully elucidated for improved mechanistic understanding of cancer immunotherapies.
    DOI:  https://doi.org/10.1016/j.ymthe.2023.11.028
  15. bioRxiv. 2023 Nov 23. pii: 2023.11.22.568379. [Epub ahead of print]
    Loss of cardiac PFKFB2 drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart.
    Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Brooke L Loveland, Albert Batushansky, Maria F Mendez Garcia, Craig Eyster, Stavros Stavrakis, Ying Ann Chiao, Michael Kinter, Kenneth M Humphries.
       Background: Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) is a critical glycolytic regulator responsible for upregulation of glycolysis in response to insulin and adrenergic signaling. PFKFB2, the cardiac isoform of PFK-2, is degraded in the heart in the absence of insulin signaling, contributing to diabetes-induced cardiac metabolic inflexibility. However, previous studies have not examined how the loss of PFKFB2 affects global cardiac metabolism and function.
    Methods: To address this, we have generated a mouse model with a cardiomyocyte-specific knockout of PFKFB2 (cKO). Using 9-month-old cKO and control (CON) mice, we characterized impacts of PFKFB2 on cardiac metabolism, function, and electrophysiology.
    Results: cKO mice have a shortened lifespan of 9 months. Metabolically, cKO mice are characterized by increased glycolytic enzyme abundance and pyruvate dehydrogenase (PDH) activity, as well as decreased mitochondrial abundance and beta oxidation, suggesting a shift toward glucose metabolism. This was supported by a decrease in the ratio of palmitoyl carnitine to pyruvate-dependent mitochondrial respiration in cKO relative to CON animals. Metabolomic, proteomic, and western blot data support the activation of ancillary glucose metabolism, including pentose phosphate and hexosamine biosynthesis pathways. Physiologically, cKO animals exhibited impaired systolic function and left ventricular (LV) dilation, represented by reduced fractional shortening and increased LV internal diameter, respectively. This was accompanied by electrophysiological alterations including increased QT interval and other metrics of delayed ventricular conduction.
    Conclusions: Loss of PFKFB2 results in metabolic remodeling marked by cardiac ancillary pathway activation. This could delineate an underpinning of pathologic changes to mechanical and electrical function in the heart.
    Clinical Perspective: What is New?: We have generated a novel cardiomyocyte-specific knockout model of PFKFB2, the cardiac isoform of the primary glycolytic regulator Phosphofructokinase-2 (cKO).The cKO model demonstrates that loss of cardiac PFKFB2 drives metabolic reprogramming and shunting of glucose metabolites to ancillary metabolic pathways.The loss of cardiac PFKFB2 promotes electrophysiological and functional remodeling in the cKO heart.What are the Clinical Implications?: PFKFB2 is degraded in the absence of insulin signaling, making its loss particularly relevant to diabetes and the pathophysiology of diabetic cardiomyopathy.Changes which we observe in the cKO model are consistent with those often observed in diabetes and heart failure of other etiologies.Defining PFKFB2 loss as a driver of cardiac pathogenesis identifies it as a target for future investigation and potential therapeutic intervention.
    DOI:  https://doi.org/10.1101/2023.11.22.568379
  16. Cold Spring Harb Perspect Med. 2023 Dec 05. pii: a041197. [Epub ahead of print]
    Aging and Inflammation.
    Amit Singh, Shepherd H Schurman, Arsun Bektas, Mary Kaileh, Roshni Roy, David M Wilson, Ranjan Sen, Luigi Ferrucci.
      Aging can be conceptualized as the progressive disequilibrium between stochastic damage accumulation and resilience mechanisms that continuously repair that damage, which eventually cause the development of chronic disease, frailty, and death. The immune system is at the forefront of these resilience mechanisms. Indeed, aging is associated with persistent activation of the immune system, witnessed by a high circulating level of inflammatory markers and activation of immune cells in the circulation and in tissue, a condition called "inflammaging." Like aging, inflammaging is associated with increased risk of many age-related pathologies and disabilities, as well as frailty and death. Herein we discuss recent advances in the understanding of the mechanisms leading to inflammaging and the intrinsic dysregulation of the immune function that occurs with aging. We focus on the underlying mechanisms of chronic inflammation, in particular the role of NF-κB and recent studies targeting proinflammatory mediators. We further explore the dysregulation of the immune response with age and immunosenescence as an important mechanistic immune response to acute stressors. We examine the role of the gastrointestinal microbiome, age-related dysbiosis, and the integrated stress response in modulating the inflammatory "response" to damage accumulation and stress. We conclude by focusing on the seminal question of whether reducing inflammation is useful and the results of related clinical trials. In summary, we propose that inflammation may be viewed both as a clinical biomarker of the failure of resilience mechanisms and as a causal factor in the rising burden of disease and disabilities with aging. The fact that inflammation can be reduced through nonpharmacological interventions such as diet and exercise suggests that a life course approach based on education may be a successful strategy to increase the health span with few adverse consequences.
    DOI:  https://doi.org/10.1101/cshperspect.a041197
  17. Nat Commun. 2023 Dec 06. 14(1): 7844
    T cell migration requires ion and water influx to regulate actin polymerization.
    Leonard L de Boer, Lesley Vanes, Serena Melgrati, Joshua Biggs O'May, Darryl Hayward, Paul C Driscoll, Jason Day, Alexander Griffiths, Renata Magueta, Alexander Morrell, James I MacRae, Robert Köchl, Victor L J Tybulewicz.
      Migration of T cells is essential for their ability to mount immune responses. Chemokine-induced T cell migration requires WNK1, a kinase that regulates ion influx into the cell. However, it is not known why ion entry is necessary for T cell movement. Here we show that signaling from the chemokine receptor CCR7 leads to activation of WNK1 and its downstream pathway at the leading edge of migrating CD4+ T cells, resulting in ion influx and water entry by osmosis. We propose that WNK1-induced water entry is required to swell the membrane at the leading edge, generating space into which actin filaments can polymerize, thereby facilitating forward movement of the cell. Given the broad expression of WNK1 pathway proteins, our study suggests that ion and water influx are likely to be essential for migration in many cell types, including leukocytes and metastatic tumor cells.
    DOI:  https://doi.org/10.1038/s41467-023-43423-8
  18. bioRxiv. 2023 Nov 21. pii: 2023.11.20.567963. [Epub ahead of print]
    A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation.
    Karl N Miller, Brightany Li, Hannah R Pierce-Hoffman, Xue Lei, Aaron P Havas, Shreeya Patel, Carolina Cano Macip, Stella G Victorelli, Seung-Hwa Woo, Anthony B Lagnado, Tianhui Liu, Nirmalya Dasgupta, Jun Lyu, Yoav Altman, Rebecca A Porritt, Guillermina Garcia, Carolin Mogler, Zhixun Dou, Chongyi Chen, João F Passos, Peter D Adams.
      Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Understanding their interrelationship will help unravel new mechanisms and therapeutic targets of aging and age-associated diseases. Here we report a novel mechanism directly linking genomic instability and inflammation in senescent cells, through a mitochondria-regulated molecular circuit that connects the p53 tumor suppressor and cytoplasmic chromatin fragments (CCF), a driver of inflammation through the cGAS-STING pathway. Activation or inactivation of p53 by genetic and pharmacologic approaches showed that p53 suppresses CCF accumulation and the downstream inflammatory senescence-associated secretory phenotype (SASP), independent of its effects on cell cycle arrest. p53 activation suppressed CCF formation by promoting DNA repair, reflected in maintenance of genomic integrity, particularly in subtelomeric regions, as shown by single cell genome resequencing. Activation of p53 by pharmacological inhibition of MDM2 in old mice decreased features of SASP in liver, indicating a senomorphic role in vivo . Remarkably, mitochondria in senescent cells suppressed p53 activity by promoting CCF formation and thereby restricting ATM-dependent nuclear DNA damage signaling. These data provide evidence for a mitochondria-regulated p53-CCF circuit in senescent cells that controls DNA repair, genome integrity and inflammatory SASP, and is a potential target for senomorphic healthy aging interventions.
    DOI:  https://doi.org/10.1101/2023.11.20.567963
  19. Nat Aging. 2023 Dec 06.
    Isoleucine dietary restriction boosts healthspan and longevity in mice.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-023-00547-2
  20. Front Immunol. 2023 ;14 1275423
    Tox induces T cell IL-10 production in a BATF-dependent manner.
    D Alejandro Canaria, J Alejandra Rodriguez, Luopin Wang, Franklin J Yeo, Bingyu Yan, Mengbo Wang, Charlotte Campbell, Majid Kazemian, Matthew R Olson.
      Tox is a member of the high mobility group (HMG)-Box transcription factors and plays important roles in thymic T cell development. Outside of the thymus, however, Tox is also highly expressed by CD8 and CD4 T cells in various states of activation and in settings of cancer and autoimmune disease. In CD4 T cells, Tox has been primarily studied in T follicular helper (TFH) cells where it, along with Tox2, promotes TFH differentiation by regulating key TFH-associated genes and suppressing CD4 cytotoxic T cell differentiation. However, the role of Tox in other T helper (Th) cell subtypes is less clear. Here, we show that Tox is expressed in several physiologically-activated Th subtypes and its ectopic expression enhances the in vitro differentiation of Th2 and T regulatory (Treg) cells. Tox overexpression in unpolarized Th cells also induced the expression of several genes involved in cell activation (Pdcd1), cellular trafficking (Ccl3, Ccl4, Xcl1) and suppressing inflammation (Il10) across multiple Th subtypes. We found that Tox binds the regulatory regions of these genes along with the transcription factors BATF, IRF4, and JunB and that Tox-induced expression of IL-10, but not PD-1, is BATF-dependent. Based on these data, we propose a model where Tox regulates Th cell chemotactic genes involved in facilitating dendritic cell-T cell interactions and aids in the resolution or prevention of inflammation through the production of IL-10.
    Keywords:  BATF/JUN/IRF4 complex; IL-10; T cell differentiation; TOX; transcription factors (TF) S
    DOI:  https://doi.org/10.3389/fimmu.2023.1275423
  21. Cell Rep. 2023 Dec 02. pii: S2211-1247(23)01542-5. [Epub ahead of print]42(12): 113530
    IL-15-dependent immune crosstalk between natural killer cells and dendritic cells in HIV-1 elite controllers.
    Ciputra Adijaya Hartana, Melanie Lancien, Ce Gao, Yelizaveta Rassadkina, Mathias Lichterfeld, Xu G Yu.
      As the principal effector cell population of the innate immune system, natural killer (NK) cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory chromatin features, we demonstrate here that cytotoxic NK (cNK) cells from elite controllers (ECs) display elevated activating histone modifications at the interleukin 2 (IL-2)/IL-15 receptor β chain and the BCL2 gene loci. These histone changes translate into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincides with higher levels of IL-15 transcription by myeloid dendritic cells in ECs. The distinct immune crosstalk between these innate immune cell populations results in improved IL-15-dependent cNK cell survival and cytotoxicity, paired with a metabolic profile biased toward IL-15-mediated glycolytic activities. Together, these results suggest that cNK cells from ECs display a programmed IL-15 response signature and support the emerging role of innate immune pathways in natural, drug-free control of HIV-1.
    Keywords:  CP: Immunology; HIV infection; IL-15; NK cells; chromatin modifications; cytotoxicity; elite controllers; metabolism; trained innate immunity
    DOI:  https://doi.org/10.1016/j.celrep.2023.113530
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