bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–01–21
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. The transcriptional cofactor Tle3 reciprocally controls effector and central memory CD8+ T cell fates.
  2. Metabolic waypoints during T cell differentiation.
  3. NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.
  4. Advances in macrophage and T cell metabolic reprogramming and immunotherapy in the tumor microenvironment.
  5. T cell dysfunctions in myelodysplastic syndromes.
  6. Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.
  7. Retracted: CD4-Targeted T Cells Rapidly Induce Remissions in Mice with T Cell Lymphoma.
  8. Neonatal CD8+ T Cells Resist Exhaustion during Chronic Infection.
  9. Aging-Related Immune Cell Phenotypes and Mortality in the Framingham Heart Study.
  10. Aging, Causes, and Rejuvenation of Hematopoietic Stem Cells.
  1. Nat Immunol. 2024 Jan 18.
    The transcriptional cofactor Tle3 reciprocally controls effector and central memory CD8+ T cell fates.
    Xin Zhao, Wei Hu, Sung Rye Park, Shaoqi Zhu, Shengen Shawn Hu, Chongzhi Zang, Weiqun Peng, Qiang Shan, Hai-Hui Xue.
      Antigen-experienced CD8+ T cells form effector and central memory T cells (TEM and TCM cells, respectively); however, the mechanism(s) controlling their lineage plasticity remains incompletely understood. Here we show that the transcription cofactor Tle3 critically regulates TEM and TCM cell fates and lineage stability through dynamic redistribution in antigen-responding CD8+ T cell genome. Genetic ablation of Tle3 promoted CD8+ TCM cell formation at the expense of CD8+ TEM cells. Lineage tracing showed that Tle3-deficient CD8+ TEM cells underwent accelerated conversion into CD8+ TCM cells while retaining robust recall capacity. Tle3 acted as a coactivator for Tbet to increase chromatin opening at CD8+ TEM cell-characteristic sites and to activate CD8+ TEM cell signature gene transcription, while engaging Runx3 and Tcf1 to limit CD8+ TCM cell-characteristic molecular features. Thus, Tle3 integrated functions of multiple transcription factors to guard lineage fidelity of CD8+ TEM cells, and manipulation of Tle3 activity could favor CD8+ TCM cell production.
    DOI:  https://doi.org/10.1038/s41590-023-01720-w
  2. Nat Immunol. 2024 Jan 18.
    Metabolic waypoints during T cell differentiation.
    Drew Wilfahrt, Greg M Delgoffe.
      This Review explores the interplay between T cell activation and cell metabolism and highlights how metabolites serve two pivotal functions in shaping the immune response. Traditionally, T cell activation has been characterized by T cell antigen receptor-major histocompatibility complex interaction (signal 1), co-stimulation (signal 2) and cytokine signaling (signal 3). However, recent research has unveiled the critical role of metabolites in this process. Firstly, metabolites act as signal propagators that aid in the transmission of core activation signals, such as specific lipid species that are crucial at the immune synapse. Secondly, metabolites also function as unique signals that influence immune differentiation pathways, such as amino acid-induced mTORC1 signaling. Metabolites also play a substantial role in epigenetic remodeling, by directly modifying histones, altering gene expression and influencing T cell behavior. This Review discusses how T cells integrate nutrient sensing with activating stimuli to shape their differentiation and sensitivity to metabolites. We underscore the integration of immunological and metabolic inputs in T cell function and suggest that metabolite availability is a fundamental determinant of adaptive immune responses.
    DOI:  https://doi.org/10.1038/s41590-023-01733-5
  3. J Cell Biochem. 2024 Jan 15.
    NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.
    Bin Ye, Yingting Pei, Lujing Wang, Dehao Meng, Yu Zhang, Shuang Zou, Henian Li, Jinying Liu, Ziying Xie, Changhong Tian, Yuqi Jiang, Yu Qiao, Xu Gao, Yanfen Zhang, Ning Ma.
      Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD+ and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD+ in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8+ T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD+ levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.
    Keywords:  SASP; cGAS-STING; mitochondria; nicotinamide mononucleotide; senescence
    DOI:  https://doi.org/10.1002/jcb.30522
  4. PeerJ. 2024 ;12 e16825
    Advances in macrophage and T cell metabolic reprogramming and immunotherapy in the tumor microenvironment.
    Hua Cheng, Yongbin Zheng.
      Macrophages and T cells in the tumor microenvironment (TME) play an important role in tumorigenesis and progression. However, TME is also characterized by metabolic reprogramming, which may affect macrophage and metabolic activity of T cells and promote tumor escape. Immunotherapy is an approach to fight tumors by stimulating the immune system in the host, but requires support and modulation of cellular metabolism. In this process, the metabolic roles of macrophages and T cells become increasingly important, and their metabolic status and interactions play a critical role in the success of immunotherapy. Therefore, understanding the metabolic state of T cells and macrophages in the TME and the impact of metabolic reprogramming on tumor therapy will help optimize subsequent immunotherapy strategies.
    Keywords:  Immunotherapy; Macrophages; Metabolic reprogramming; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.7717/peerj.16825
  5. Blood. 2024 Jan 18. pii: blood.2023023166. [Epub ahead of print]
    T cell dysfunctions in myelodysplastic syndromes.
    Juan Jose Rodriguez-Sevilla, Simona Colla.
      Escape from immune surveillance is a hallmark of cancer. Immune deregulation caused by intrinsic and extrinsic cellular factors, such as altered T cell functions, leads to immune exhaustion, loss of immune surveillance, and clonal proliferation of tumoral cells. The T cell immune system contributes to the pathogenesis, maintenance, and progression of myelodysplastic syndrome (MDS). Here, we comprehensively reviewed our current biological knowledge of the T cell compartment in MDS and recent advances in the development of immunotherapeutic strategies, such as immune checkpoint inhibitors and T cell- and antibody-based adoptive therapies, that hold promise to improve the outcome of MDS patients.
    DOI:  https://doi.org/10.1182/blood.2023023166
  6. Cell Metab. 2024 Jan 13. pii: S1550-4131(23)00467-9. [Epub ahead of print]
    Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity.
    Jia-Yao Fu, Shi-Jia Huang, Bao-Li Wang, Jun-Hao Yin, Chang-Yu Chen, Jia-Bao Xu, Yan-Lin Chen, Shuo Xu, Ting Dong, Hao-Nan Zhou, Xin-Yi Ma, Yi-Ping Pu, Hui Li, Xiu-Juan Yang, Li-Song Xie, Zhi-Jun Wang, Qi Luo, Yan-Xiong Shao, Lei Ye, Zi-Rui Zong, Xin-Di Wei, Wan-Wen Xiao, Shu-Tong Niu, Yi-Ming Liu, He-Ping Xu, Chuang-Qi Yu, Sheng-Zhong Duan, Ling-Yan Zheng.
      Augmented CD4+ T cell response in autoimmunity is characterized by extensive metabolic reprogramming. However, the epigenetic molecule that drives the metabolic adaptation of CD4+ T cells remains largely unknown. Here, we show that lysine acetyltransferase 6A (KAT6A), an epigenetic modulator that is clinically associated with autoimmunity, orchestrates the metabolic reprogramming of glucose in CD4+ T cells. KAT6A is required for the proliferation and differentiation of proinflammatory CD4+ T cell subsets in vitro, and mice with KAT6A-deficient CD4+ T cells are less susceptible to experimental autoimmune encephalomyelitis and colitis. Mechanistically, KAT6A orchestrates the abundance of histone acetylation at the chromatin where several glycolytic genes are located, thus affecting glucose metabolic reprogramming and subsequent CD4+ T cell responses. Treatment with KAT6A small-molecule inhibitors in mouse models shows high therapeutic value for targeting KAT6A in autoimmunity. Our study provides novel insights into the epigenetic programming of immunometabolism and suggests potential therapeutic targets for patients with autoimmunity.
    Keywords:  KAT6A; T helper 17 cells; autoimmune; effector T cell response; glucose metabolism; histone acetylation
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.016
  7. Biomed Res Int. 2024 ;2024 9763543
    Retracted: CD4-Targeted T Cells Rapidly Induce Remissions in Mice with T Cell Lymphoma.
    BioMed Research International.
      [This retracts the article DOI: 10.1155/2021/6614784.].
    DOI:  https://doi.org/10.1155/2024/9763543
  8. J Immunol. 2024 Jan 17. pii: ji2300396. [Epub ahead of print]
    Neonatal CD8+ T Cells Resist Exhaustion during Chronic Infection.
    Viviana I Maymí, Hongya Zhu, Mason Jager, Shawn Johnson, Rodman Getchell, James W Casey, Jennifer K Grenier, E John Wherry, Norah L Smith, Andrew Grimson, Brian D Rudd.
      Chronic viral infections, such as HIV and hepatitis C virus, represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral infections, the underlying mechanisms remain unknown. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (lymphocytic choriomeningitis virus clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially became effector cells early in chronic infection compared with adult CD8+ T cells and expressed higher levels of genes associated with cell migration and effector cell differentiation. During the chronic phase of infection, the neonatal cells retained more immune functionality and expressed lower levels of surface markers and genes related to exhaustion. Because the neonatal cells protect from viral replication early in chronic infection, the altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influence key cell fate decisions during chronic infection.
    DOI:  https://doi.org/10.4049/jimmunol.2300396
  9. Res Sq. 2023 Dec 26. pii: rs.3.rs-3773986. [Epub ahead of print]
    Aging-Related Immune Cell Phenotypes and Mortality in the Framingham Heart Study.
    Ahmed A Y Ragab, Margaret F Doyle, Jiachen Chen, Yuan Fang, Kathryn L Lunetta, Joanne M Murabito.
      Background The global increase in human life expectancy is evident. The total number of individuals aged 60 or above is anticipated to reach 2 billion by 2050. Aging, an inherently complex process, manifests prominently in the changes observed in the immune system. A notable marker of immune system aging is the presence of Aging-Related Immune Cell Phenotypes (ARIPs). Despite their significance, the connections between various ARIPs and mortality have not been thoroughly investigated. We prospectively investigated 16 different ARIPs using flow cytometry, namely, CD4/CD8 ratio, Granzyme B + CD8/Granyzme B + CD4, T N /T M = Tn / (Teff + Tem + Tcm) for T N /T M CD4 + and T N /T M CD8 + ratios, Th17/CD4 + Treg, Tc17/CD8 + Treg, Th17, Tc17, CD4 + Temra, CD8 + Temra, CD4 + CD25 + FoxP3+ (CD4 + Treg), CD8 + CD25 + FoxP3+ (CD8 + Treg) CD4 + CD27-, CD4 + CD28-CD27-, CD8 + CD27-, CD8 + CD28-CD27- and IL-6 in relation to survival outcome among dementia-free Framingham Heart Study (FHS) offspring cohort participants who attended the seventh exam (1998-2001). Results Among 996 participants (mean age 62 years, range 40 to 88 years, 52% female), the survival rate was 65% during 19 years of follow-up. For the model adjusting for age, sex, and cytomegalovirus (CMV) serostatus, higher CD4/CD8 and Tc17/CD8 + Treg ratios were significantly associated with lower all-cause mortality (HR:0.86 [0.76-0.96], 0.84 [0.74-0.94], respectively) and higher CD8 regulatory cell levels (CD8 + CD25 + FoxP3+) were associated with higher all-cause mortality (HR = 1.17, [1.03-1.32]). Higher IL-6 levels were associated with higher all-cause, cardiovascular, and non-cardiovascular mortality (HR = 1.43 [1.26-1.62], 1.70 [1.31-2.21], and 1.36 [1.18-1.57], respectively).
    DOI:  https://doi.org/10.21203/rs.3.rs-3773986/v1
  10. Adv Exp Med Biol. 2023 ;1442 201-210
    Aging, Causes, and Rejuvenation of Hematopoietic Stem Cells.
    Zhiyang Chen, Zhenyu Ju, Yan Sun.
      Hematopoietic stem cells (HSCs) undergo an age-related functional decline, which leads to a disruption of the blood system and contributes to the development of aging-associated hematopoietic diseases and malignancies. In this section, we provide a summary of the key hallmarks associated with HSC aging. We also examine the causal factors that contribute to HSC aging and emphasize potential approaches to mitigate HSC aging and age-related hematopoietic disorders.
    Keywords:  Aging; HSC; Niche; Therapeutic strategies
    DOI:  https://doi.org/10.1007/978-981-99-7471-9_12
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