bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–07–28
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Mitochondrial Transplantation Promotes Protective Effector and Memory CD4+ T Cell Response During Mycobacterium Tuberculosis Infection and Diminishes Exhaustion and Senescence in Elderly CD4+ T cells.
  2. The ATP-exporting channel Pannexin 1 promotes CD8+ T cell effector and memory responses.
  3. An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
  4. CRISPR-based genetic screens advance cancer immunology.
  5. Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
  6. Enhancing the activation of T cells through anti-CD3/CD28 magnetic beads by adjusting the antibody ratio.
  7. Thymic microenvironment's impact on immunosenescence.
  8. Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation.
  1. Adv Sci (Weinh). 2024 Jul 22. e2401077
    Mitochondrial Transplantation Promotes Protective Effector and Memory CD4+ T Cell Response During Mycobacterium Tuberculosis Infection and Diminishes Exhaustion and Senescence in Elderly CD4+ T cells.
    Colwyn A Headley, Shalini Gautam, Angelica Olmo-Fontanez, Andreu Garcia-Vilanova, Varun Dwivedi, Alyssa Schami, Susan Weintraub, Philip S Tsao, Jordi B Torrelles, Joanne Turner.
      Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is a major global health concern, particularly affecting those with weakened immune systems, including the elderly. CD4+ T cell response is crucial for immunity against M.tb, but chronic infections and aging can lead to T cell exhaustion and senescence, worsening TB disease. Mitochondrial dysfunction, prevalent in aging and chronic diseases, disrupts cellular metabolism, increases oxidative stress, and impairs T-cell functions. This study investigates the effect of mitochondrial transplantation (mito-transfer) on CD4+ T cell differentiation and function in aged mouse models and human CD4+ T cells from elderly individuals. Mito-transfer in naïve CD4+ T cells is found to promote protective effector and memory T cell generation during M.tb infection in mice. Additionally, it improves elderly human T cell function by increasing mitochondrial mass and altering cytokine production, thereby reducing markers of exhaustion and senescence. These findings suggest mito-transfer as a novel approach to enhance aged CD4+ T cell functionality, potentially benefiting immune responses in the elderly and chronic TB patients. This has broader implications for diseases where mitochondrial dysfunction contributes to T-cell exhaustion and senescence.
    Keywords:  CD4+ T Cells; T cell exhaustion; T cell senescence; cellular reprogramming; immune aging; immunometabolism; mitochondrial dysfunction; mitochondrial reprogramming; mitochondrial transplantation; oxidative stress; tuberculosis
    DOI:  https://doi.org/10.1002/advs.202401077
  2. iScience. 2024 Jul 19. 27(7): 110290
    The ATP-exporting channel Pannexin 1 promotes CD8+ T cell effector and memory responses.
    Trupti Vardam-Kaur, Alma Banuelos, Maria Gabaldon-Parish, Bruna Gois Macedo, Caio Loureiro Salgado, Kelsey Marie Wanhainen, Maggie Hanqi Zhou, Sarah van Dijk, Igor Santiago-Carvalho, Angad S Beniwal, Chloe L Leff, Changwei Peng, Nhan L Tran, Stephen C Jameson, Henrique Borges da Silva.
      Sensing of extracellular ATP (eATP) controls CD8+ T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin 1 (Panx1). Whether Panx1 controls CD8+ T cell immune responses in vivo, however, has not been previously addressed. Here, we report that T-cell-specific Panx1 is needed for CD8+ T cell responses to viral infections and cancer. We found that CD8-specific Panx1 promotes both effector and memory CD8+ T cell responses. Panx1 favors initial effector CD8+ T cell activation through extracellular ATP (eATP) export and subsequent P2RX4 activation, which helps promote full effector differentiation through extracellular lactate accumulation and its subsequent recycling. In contrast, Panx1 promotes memory CD8+ T cell survival primarily through ATP export and subsequent P2RX7 engagement, leading to improved mitochondrial metabolism. In summary, Panx1-mediated eATP export regulates effector and memory CD8+ T cells through distinct purinergic receptors and different metabolic and signaling pathways.
    Keywords:  Biochemistry; Biological sciences; Immune response; Immune system; Immunology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.110290
  3. Nat Aging. 2024 Jul 23.
    An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
    Zehan Song, Sang Hee Park, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang, Anita Wong Lin, Kartoosh Heydari, Claudia C S Chini, Eduardo N Chini, Cholsoon Jang, Danica Chen.
      How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.
    DOI:  https://doi.org/10.1038/s43587-024-00670-8
  4. Sci China Life Sci. 2024 Jul 23.
    CRISPR-based genetic screens advance cancer immunology.
    Yuanfang Cao, Xueting Li, Yumu Pan, Huahe Wang, Siyu Yang, Lingjuan Hong, Lupeng Ye.
      CRISPR technologies have revolutionized research areas ranging from fundamental science to translational medicine. CRISPR-based genetic screens offer a powerful platform for unbiased screening in various fields, such as cancer immunology. Immune checkpoint blockade (ICB) therapy has been shown to strongly affect cancer treatment. However, the currently available ICBs are limited and do not work in all cancer patients. Pooled CRISPR screens enable the identification of previously unknown immune regulators that can regulate T-cell activation, cytotoxicity, persistence, infiltration into tumors, cytokine secretion, memory formation, T-cell metabolism, and CD4+ T-cell differentiation. These novel targets can be developed as new immunotherapies or used with the current ICBs as new combination therapies that may yield synergistic efficacy. Here, we review the progress made in the development of CRISPR technologies, particularly technological advances in CRISPR screens and their application in novel target identification for immunotherapy.
    Keywords:  CRISPR/Cas; cancer immunotherapy; gene editing; genetic screening; immune cells
    DOI:  https://doi.org/10.1007/s11427-023-2571-0
  5. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00825-8. [Epub ahead of print] 114496
    Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
    Kan Etoh, Hirotaka Araki, Tomoaki Koga, Yuko Hino, Kanji Kuribayashi, Shinjiro Hino, Mitsuyoshi Nakao.
      The senescent microenvironment and aged cells per se contribute to tissue remodeling, chronic inflammation, and age-associated dysfunction. However, the metabolic and epigenomic bases of the senescence-associated secretory phenotype (SASP) remain largely unknown. Here, we show that ATP-citrate lyase (ACLY), a key enzyme in acetyl-coenzyme A (CoA) synthesis, is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.
    Keywords:  ACLY; CP: Cell biology; CP: Metabolism; H3K27 acetylation; SASP; acetyl-CoA; citrate metabolism; senescence; senostatics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114496
  6. IUBMB Life. 2024 Jul 24.
    Enhancing the activation of T cells through anti-CD3/CD28 magnetic beads by adjusting the antibody ratio.
    Yinuo Chen, Rui Zhao, Qi Fan, Mengmeng Liu, Yonglin Huang, Guoqing Shi.
      The utilization of anti-CD3/CD28 magnetic beads for T cell expansion in vitro has been investigated for adoptive cell transfer therapy. However, the impact of the CD3/CD28 antibody ratio on T cell differentiation and function remains incompletely elucidated. This study seeks to address this knowledge gap. To begin with, CD3 antibodies with a relatively low avidity for Jurkat cells (Kd = 13.55 nM) and CD28 antibodies with a relatively high avidity (Kd = 5.79 nM) were prepared. Afterwards, anti-CD3/CD28 antibodies with different mass ratios were attached to magnetic beads to examine the impacts of different antibody ratios on T cell capture, and proliferation. The research demonstrated that the most significant expansion of T cells was stimulated by the anti-CD3/CD28 magnetic beads with a mass ratio of 2:1 for CD3 antibodies and CD28 antibodies. Moreover, CD25 and PD1 expression of expanded T cells increased and then decreased, with lower CD25 and PD1 expression in the later stages of expansion indicating that T cells were not depleted. These T cells, which are massively expanded in vitro and have excellent expansion potential, can be infused back into the patient to treat tumor patients. This study shows that altering the ratio of anti-CD3/CD28 antibodies can control the strength of T cell stimulation, thereby leading to the improvement of T cell activation. This discovery can be utilized as a guide for the creation of other T cell stimulation approaches, which is beneficial for the further development of tumor immunotherapy technology.
    Keywords:  anti‐CD3/CD28 magnetic beads; different mass ratios; ex vivo T‐cell expansion
    DOI:  https://doi.org/10.1002/iub.2898
  7. Immunol Res. 2024 Jul 23.
    Thymic microenvironment's impact on immunosenescence.
    Li Li, Feng Xu, Yi Han, Jun Zeng, Shan Du, Changshan Wang.
      Age-related thymic involution is characterized by the loss of T cell development and the supporting epithelial network, which are replaced by adipose tissue. We previously showed that aging functionally impairs lymphohematopoietic progenitor cells, including thymic early T cell progenitors (ETPs), contributing to thymic involution. Considering that the thymic microenvironment is essential for thymocyte incubation, we aimed to investigate its role in age-related thymic involution and the mechanisms underlying these changes. The challenge in studying these processes led us to transplant T cell-depleted fetal thymus tissue into the kidney capsule of aged mice. This model allowed us to identify the mechanisms driving age-related changes in the thymic microenvironment and to assess whether these changes could be reversed. Flow cytometry was used to detect naïve T cells (CD62L+CD44-), including CD4 CD8 double-negative, double-positive, and single-positive T cells. Real-time PCR was used to detect and quantify signal-joint T cell receptor excision circles. We rearranged δRec-ΨJα in murine peripheral blood leukocytes to evaluate the thymic output of newly developed naïve T cells in the mice and gene expression in the thymus. Age-related thymic involution decreased naïve T cells and increased memory T cells, while fetal thymus transplantation improved thymic output and T cell production and reversed the impairment of thymopoiesis due to thymic involution in aged mice. Furthermore, the expression of key cytokines was restored and ETPs in the aged mice showed normal thymic T cell development. Our study suggests that degenerative changes in the thymic microenvironment are the primary cause of thymic dysfunction, leading to immunosenescence associated with age-related thymic involution.
    Keywords:  Age-related thymic involution; Immunosenescence; Thymic epithelial cells; Thymic microenvironment; Thymopoiesis
    DOI:  https://doi.org/10.1007/s12026-024-09519-z
  8. Immunity. 2024 Jul 16. pii: S1074-7613(24)00320-0. [Epub ahead of print]
    Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation.
    Frank A Buquicchio, Raissa Fonseca, Patrick K Yan, Fangyi Wang, Maximilien Evrard, Andreas Obers, Jacob C Gutierrez, Colin J Raposo, Julia A Belk, Bence Daniel, Pirooz Zareie, Kathryn E Yost, Yanyan Qi, Yajie Yin, Katherine F Nico, Flora M Tierney, Michael R Howitt, Caleb A Lareau, Ansuman T Satpathy, Laura K Mackay.
      The memory CD8+ T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8+ T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (TRM) cells and circulating memory T (TCIRC) cells develop along distinct epigenetic trajectories. We identified organ-specific transcriptional regulators of TRM cell development, including FOSB, FOS, FOSL1, and BACH2, and defined an epigenetic signature common to TRM cells across organs. Finally, we found that although terminal TEX cells share accessible regulatory elements with TRM cells, they are defined by TEX-specific epigenetic features absent from TRM cells. Together, this comprehensive data resource shows that TRM cell development is accompanied by dynamic transcriptome alterations and chromatin accessibility changes that direct tissue-adapted and functionally distinct T cell states.
    Keywords:  chromatin accessibility; development; epigenetics; regulatory elements; single-cell genomics; tissue immunity; tissue-resident memory T cells; transcriptional regulators
    DOI:  https://doi.org/10.1016/j.immuni.2024.06.014
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