bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–08–18
thirteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities.
  2. ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.
  3. Autocrine VEGF-B signaling maintains lipid synthesis and mitochondrial fitness to support T cell immune responses.
  4. Rejuvenation Strategy for Inducing and Enhancing Autoimmune Response to Eliminate Senescent Cells.
  5. The influence of metabolic disorders on adaptive immunity.
  6. LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity.
  7. The dynamics and longevity of circulating CD4+ memory T cells depend on cell age and not the chronological age of the host.
  8. Cutting Edge: Retinoic Acid Promotes Brain-homing of CD8+ T Cells during Congenital Cytomegalovirus Infection.
  9. Immunosenescence: A new direction in anti-aging research.
  10. LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity.
  11. Mitochondrial complex I promotes kidney cancer metastasis.
  12. The connection between aging, cellular senescence and gut microbiome alterations: A comprehensive review.
  13. Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity.
  1. Sci Immunol. 2024 Aug 16. 9(98): eadh0368
    Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities.
    Andrew R Patterson, Gabriel A Needle, Ayaka Sugiura, Erin Q Jennings, Channing Chi, KayLee K Steiner, Emilie L Fisher, Gabriella L Robertson, Caroline Bodnya, Janet G Markle, Ryan D Sheldon, Russell G Jones, Vivian Gama, Jeffrey C Rathmell.
      Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable previously unappreciated crossover. Analysis of IEMs showed that N-linked glycosylation and the hexosamine pathway enzyme Gfpt1 are critical for T cell expansion and function. Further, T helper (TH1) cells synthesized uridine diphosphate N-acetylglucosamine more rapidly and were more impaired by Gfpt1 deficiency than TH17 cells. Screening IEI genes found that Bcl11b promotes the CD4 T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. Thus, a high degree of functional overlap exists between IEM and IEI genes, and immunometabolic mechanisms may underlie a previously underappreciated intersection of these disorders.
    DOI:  https://doi.org/10.1126/sciimmunol.adh0368
  2. J Exp Med. 2024 Sep 02. pii: e20231820. [Epub ahead of print]221(9):
    ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.
    Irem Kaymak, McLane J Watson, Brandon M Oswald, Shixin Ma, Benjamin K Johnson, Lisa M DeCamp, Batsirai M Mabvakure, Katarzyna M Luda, Eric H Ma, Kin Lau, Zhen Fu, Brejnev Muhire, Susan M Kitchen-Goosen, Alexandra Vander Ark, Michael S Dahabieh, Bozena Samborska, Matthew Vos, Hui Shen, Zi Peng Fan, Thomas P Roddy, Gillian A Kingsbury, Cristovão M Sousa, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Susan M Kaech, Dominic G Roy, Russell G Jones.
      Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.
    DOI:  https://doi.org/10.1084/jem.20231820
  3. J Clin Invest. 2024 Aug 15. pii: e176586. [Epub ahead of print]134(16):
    Autocrine VEGF-B signaling maintains lipid synthesis and mitochondrial fitness to support T cell immune responses.
    Jianli He, Yalan Chen, Huihua Ding, Jin-An Zhou, Zhengcao Xing, Xinyu Yang, Qiuju Fan, Yong Zuo, Tianshi Wang, Jinke Cheng.
      T cells rewire their metabolic activities to meet the demand of immune responses, but how to coordinate the immune response by metabolic regulators in activated T cells is unknown. Here, we identified autocrine VEGF-B as a metabolic regulator to control lipid synthesis and maintain the integrity of the mitochondrial inner membrane for the survival of activated T cells. Disruption of autocrine VEGF-B signaling in T cells reduced cardiolipin mass, resulting in mitochondrial damage, with increased apoptosis and reduced memory development. The addition of cardiolipin or modulating VEGF-B signaling improved T cell mitochondrial fitness and survival. Autocrine VEGF-B signaling through GA-binding protein α (GABPα) induced sentrin/SUMO-specific protease 2 (SENP2) expression, which further de-SUMOylated PPARγ and enhanced phospholipid synthesis, leading to a cardiolipin increase in activated T cells. These data suggest that autocrine VEGF-B mediates a signal to coordinate lipid synthesis and mitochondrial fitness with T cell activation for survival and immune response. Moreover, autocrine VEGF-B signaling in T cells provides a therapeutic target against infection and tumors as well as an avenue for the treatment of autoimmune diseases.
    Keywords:  Adaptive immunity; Growth factors; Immunology; T cells
    DOI:  https://doi.org/10.1172/JCI176586
  4. Aging Dis. 2024 Jul 23.
    Rejuvenation Strategy for Inducing and Enhancing Autoimmune Response to Eliminate Senescent Cells.
    Xingyue Wang, Chengyu Zhang, Jiahong Su, Siqi Ren, Xiang Wang, Yinping Zhang, Zijun Yuan, Xinyu He, Xu Wu, Mingxing Li, Fukuan Du, Yu Chen, Shuai Deng, Yueshui Zhao, Xiaodong Wang, Yuhong Sun, Jing Shen, Huijiao Ji, Yunqing Hou, Zhangang Xiao.
      The process of aging, which involves progressive changes in the body over time, is closely associated with the development of age-related diseases. Cellular senescence is a pivotal hallmark and mechanism of the aging process. The accumulation of senescent cells can significantly contribute to the onset of age-related diseases, thereby compromising overall health. Conversely, the elimination of senescent cells enhances the body's regenerative and reparative capacity, thereby retarding the aging process. Here, we present a brief overview of 12 Hallmarks of aging and subsequently emphasize the potential of immune checkpoint blockade, innate immune cell therapy (including T cells, iNKT cells, macrophages, and NK cells), as well as CAR-T cell therapy for inducing and augmenting immune responses aimed at eliminating senescent cells. In addition to CAR-T cells, we also explore the possibility of engineered immune cells such as CAR-NK and CAR-M cells to eliminate senescent cells. In summary, immunotherapy, as an emerging strategy for the treatment of aging, offers new prospects for age-related research.
    DOI:  https://doi.org/10.14336/AD.2024.0579
  5. Cell Mol Immunol. 2024 Aug 12.
    The influence of metabolic disorders on adaptive immunity.
    Thomas J C Collins, Pooranee K Morgan, Kevin Man, Graeme I Lancaster, Andrew J Murphy.
      The immune system plays a crucial role in protecting the body from invading pathogens and maintaining tissue homoeostasis. Maintaining homoeostatic lipid metabolism is an important aspect of efficient immune cell function and when disrupted immune cell function is impaired. There are numerous metabolic diseases whereby systemic lipid metabolism and cellular function is impaired. In the context of metabolic disorders, chronic inflammation is suggested to be a major contributor to disease progression. A major contributor to tissue dysfunction in metabolic disease is ectopic lipid deposition, which is generally caused by diet and genetic factors. Thus, we propose the idea, that similar to tissue and organ damage in metabolic disorders, excessive accumulation of lipid in immune cells promotes a dysfunctional immune system (beyond the classical foam cell) and contributes to disease pathology. Herein, we review the evidence that lipid accumulation through diet can modulate the production and function of immune cells by altering cellular lipid content. This can impact immune cell signalling, activation, migration, and death, ultimately affecting key aspects of the immune system such as neutralising pathogens, antigen presentation, effector cell activation and resolving inflammation.
    Keywords:  Cancer; Cell Metabolism; Immunity; Immunometabolism; Lipid Metabolism; Metabolic Disorders
    DOI:  https://doi.org/10.1038/s41423-024-01206-1
  6. Cell. 2024 Aug 08. pii: S0092-8674(24)00776-1. [Epub ahead of print]187(16): 4355-4372.e22
    LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity.
    Lawrence P Andrews, Samuel C Butler, Jian Cui, Anthony R Cillo, Carly Cardello, Chang Liu, Erin A Brunazzi, Andrew Baessler, Bingxian Xie, Sheryl R Kunning, Shin Foong Ngiow, Yinghui Jane Huang, Sasikanth Manne, Arlene H Sharpe, Greg M Delgoffe, E John Wherry, John M Kirkwood, Tulia C Bruno, Creg J Workman, Dario A A Vignali.
      Overcoming immune-mediated resistance to PD-1 blockade remains a major clinical challenge. Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) treatment, the first in its class to be FDA approved. However, how these two inhibitory receptors synergize to hinder anti-tumor immunity remains unknown. Here, we show that CD8+ T cells deficient in both PD-1 and LAG-3, in contrast to CD8+ T cells lacking either receptor, mediate enhanced tumor clearance and long-term survival in mouse models of melanoma. PD-1- and LAG-3-deficient CD8+ T cells were transcriptionally distinct, with broad TCR clonality and enrichment of effector-like and interferon-responsive genes, resulting in enhanced IFN-γ release indicative of functionality. LAG-3 and PD-1 combined to drive T cell exhaustion, playing a dominant role in modulating TOX expression. Mechanistically, autocrine, cell-intrinsic IFN-γ signaling was required for PD-1- and LAG-3-deficient CD8+ T cells to enhance anti-tumor immunity, providing insight into how combinatorial targeting of LAG-3 and PD-1 enhances efficacy.
    Keywords:  CD8(+) T cell; IFN-γ; NKG2A; anti-LAG-3; anti-PD-1; anti-tumor immunity; immune checkpoint inhibitor; immuno-oncology; immunotherapy; melanoma
    DOI:  https://doi.org/10.1016/j.cell.2024.07.016
  7. PLoS Biol. 2024 Aug;22(8): e3002380
    The dynamics and longevity of circulating CD4+ memory T cells depend on cell age and not the chronological age of the host.
    M Elise Bullock, Thea Hogan, Cayman Williams, Sinead Morris, Maria Nowicka, Minahil Sharjeel, Christiaan van Dorp, Andrew J Yates, Benedict Seddon.
      Quantifying the kinetics with which memory T cell populations are generated and maintained is essential for identifying the determinants of the duration of immunity. The quality and persistence of circulating CD4 effector memory (TEM) and central memory (TCM) T cells in mice appear to shift with age, but it is unclear whether these changes are driven by the aging host environment, by cell age effects, or both. Here, we address these issues by combining DNA labelling methods, established fate-mapping systems, a novel reporter mouse strain, and mathematical models. Together, these allow us to quantify the dynamics of both young and established circulating memory CD4 T cell subsets, within both young and old mice. We show that that these cells and their descendents become more persistent the longer they reside within the TCM and TEM pools. This behaviour may limit memory CD4 T cell diversity by skewing TCR repertoires towards clones generated early in life, but may also compensate for functional defects in new memory cells generated in old age.
    DOI:  https://doi.org/10.1371/journal.pbio.3002380
  8. J Immunol. 2024 Aug 12. pii: ji2400150. [Epub ahead of print]
    Cutting Edge: Retinoic Acid Promotes Brain-homing of CD8+ T Cells during Congenital Cytomegalovirus Infection.
    Zachary T Hilt, Wisler Charles, Taha Ali, Casey V Smith, Shide Zhang, Samantha P Wesnak, Norah L Smith, Brian D Rudd.
      The most common congenital viral infection is CMV, which leads to numerous neurologic disabilities. Using a mouse model of congenital CMV, we previously determined that Ag-specific CD8+ T cells traffic to the brain in a CCR9-dependent manner. The mechanism by which these CD8+ T cells acquire a CCR9-dependent "brain-tropic" phenotype remains unclear. In this study, we identify the key factor that imprints brain homing specificity on CD8+ T cells, the source of production, and the location where CCR9 expression is induced. Specifically, we discovered that CCR9 is induced on CD8+ T cells by retinoic acid-producing CD8α+ dendritic cells in the cervical lymph node postinfection. We found that retinoic acid is important for CD8+ T cells to establish tissue residency in the brain. Collectively, our data expand the role of retinoic acid during infection and mechanistically demonstrate how CD8+ T cells are primed to protect the brain during congenital viral infection.
    DOI:  https://doi.org/10.4049/jimmunol.2400150
  9. Int Immunopharmacol. 2024 Aug 12. pii: S1567-5769(24)01421-8. [Epub ahead of print]141 112900
    Immunosenescence: A new direction in anti-aging research.
    Hanzhou Li, Shan Lin, Yuming Wang, Yuexuan Shi, Xixing Fang, Jida Wang, Huantian Cui, Yuhong Bian, Xin Qi.
      The immune system is a major regulatory system of the body, that is composed of immune cells, immune organs, and related signaling factors. As an organism ages, observable age-related changes in the function of the immune system accumulate in a process described as 'immune aging. Research has shown that the impact of aging on immunity is detrimental, with various dysregulated responses that affect the function of immune cells at the cellular level. For example, increased aging has been shown to result in the abnormal chemotaxis of neutrophils and decreased phagocytosis of macrophages. Age-related diminished functionality of immune cell types has direct effects on host fitness, leading to poorer responses to vaccination, more inflammation and tissue damage, as well as autoimmune disorders and the inability to control infections. Similarly, age impacts the function of the immune system at the organ level, resulting in decreased hematopoietic function in the bone marrow, a gradual deficiency of catalase in the thymus, and thymic atrophy, resulting in reduced production of related immune cells such as B cells and T cells, further increasing the risk of autoimmune disorders in the elderly. As the immune function of the body weakens, aging cells and inflammatory factors cannot be cleared, resulting in a cycle of increased inflammation that accumulates over time. Cumulatively, the consequences of immune aging increase the likelihood of developing age-related diseases, such as Alzheimer's disease, atherosclerosis, and osteoporosis, among others. Therefore, targeting the age-related changes that occur within cells of the immune system might be an effective anti-aging strategy. In this article, we summarize the relevant literature on immune aging research, focusing on its impact on aging, in hopes of providing new directions for anti-aging research.
    Keywords:  Age-related diseases; Aging; Anti-aging; Immune system; Immunosenescence
    DOI:  https://doi.org/10.1016/j.intimp.2024.112900
  10. Cell. 2024 Aug 08. pii: S0092-8674(24)00778-5. [Epub ahead of print]187(16): 4336-4354.e19
    LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity.
    Shin Foong Ngiow, Sasikanth Manne, Yinghui Jane Huang, Tarek Azar, Zeyu Chen, Divij Mathew, Qingzhou Chen, Omar Khan, Jennifer E Wu, Victor Alcalde, Ahron J Flowers, Sean McClain, Amy E Baxter, Makoto Kurachi, Junwei Shi, Alexander C Huang, Josephine R Giles, Arlene H Sharpe, Dario A A Vignali, E John Wherry.
      Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). Tex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigoration and enhanced disease control can be achieved by co-targeting multiple IRs including PD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathways are disrupted, we investigated the impact of loss of PD-1 and/or LAG-3 on Tex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and Tex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2+ subset of Tex cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b, with similar observations in humans. These analyses disentangle the non-redundant mechanisms of PD-1 and LAG-3 and their synergy in regulating Tex cells.
    Keywords:  CD94; LAG-3; NKG2; NKG2A; PD-1; Qa-1b; T cell exhaustion; TOX; cancer; immunosurveillance
    DOI:  https://doi.org/10.1016/j.cell.2024.07.018
  11. Nature. 2024 Aug 14.
    Mitochondrial complex I promotes kidney cancer metastasis.
    Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S Vu, Varun Sondhi, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, McKenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis McDaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J DeBerardinis.
      Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.
    DOI:  https://doi.org/10.1038/s41586-024-07812-3
  12. Aging Cell. 2024 Aug 15. e14315
    The connection between aging, cellular senescence and gut microbiome alterations: A comprehensive review.
    Dong-Hyun Jang, Ji-Won Shin, Eunha Shim, Naoko Ohtani, Ok Hee Jeon.
      The intricate interplay between cellular senescence and alterations in the gut microbiome emerges as a pivotal axis in the aging process, increasingly recognized for its contribution to systemic inflammation, physiological decline, and predisposition to age-associated diseases. Cellular senescence, characterized by a cessation of cell division in response to various stressors, induces morphological and functional changes within tissues. The complexity and heterogeneity of senescent cells, alongside the secretion of senescence-associated secretory phenotype, exacerbate the aging process through pro-inflammatory pathways and influence the microenvironment and immune system. Concurrently, aging-associated changes in gut microbiome diversity and composition contribute to dysbiosis, further exacerbating systemic inflammation and undermining the integrity of various bodily functions. This review encapsulates the burgeoning research on the reciprocal relationship between cellular senescence and gut dysbiosis, highlighting their collective impact on age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and osteoarthritis. It also explores the potential of modulating the gut microbiome and targeting cellular senescence as innovative strategies for healthy aging and mitigating the progression of aging-related conditions. By exploring targeted interventions, including the development of senotherapeutic drugs and probiotic therapies, this review aims to shed light on novel therapeutic avenues. These strategies leverage the connection between cellular senescence and gut microbiome alterations to advance aging research and development of interventions aimed at extending health span and improving the quality of life in the older population.
    Keywords:  aging; cellular senescence; gut microbiome; musculoskeletal diseases; senotherapeutics
    DOI:  https://doi.org/10.1111/acel.14315
  13. Cell. 2024 Aug 08. pii: S0092-8674(24)00710-4. [Epub ahead of print]187(16): 4373-4388.e15
    Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity.
    Anthony R Cillo, Carly Cardello, Feng Shan, Lilit Karapetyan, Sheryl Kunning, Cindy Sander, Elizabeth Rush, Arivarasan Karunamurthy, Ryan C Massa, Anjali Rohatgi, Creg J Workman, John M Kirkwood, Tullia C Bruno, Dario A A Vignali.
      Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.
    Keywords:  CD8(+) T cell transcriptional profiles; LAG-3; PD-1; T cell exhaustion; advanced melanoma; antitumor immunity; checkpoint blockade; combination immunotherapy; inhibitory receptors
    DOI:  https://doi.org/10.1016/j.cell.2024.06.036
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:17.