bims-imseme 2025-01-12 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–01–12
ten papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Targeted localization of the mother centrosome in CD8+ T cells undergoing asymmetric cell division promotes memory formation.
Protein Phosphatase 2A Promotes CD8+ T Cell Effector Function through the Augmentation of CD28 Costimulation.
Glucose Metabolism Reprogramming of Immune Cells in the Microenvironment of Pancreatic and Hepatobiliary Cancers.
Precursors of exhausted T cells are preemptively formed in acute infection.
Immunosenescence: Aging and Immune System Decline.
Anti-CTLA-4 generates greater memory response than anti-PD-1 via TCF-1.
Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia.
Magnesium peroxide-based biomimetic nanoigniter degrades extracellular matrix to awake T cell-mediated cancer immunotherapy.
An early precursor CD8 T cell that adapts to acute or chronic viral infection.
How age affects human hematopoietic stem and progenitor cells and strategies to mitigate HSPC aging.

Cell Rep. 2025 Jan 06. pii: S2211-1247(24)01478-5. [Epub ahead of print]44(1): 115127

Targeted localization of the mother centrosome in CD8+ T cells undergoing asymmetric cell division promotes memory formation.

Niculò Barandun, Benjamin Meier, Gautier Stehli, Fabienne Gräbnitz, Nathan Zangger, Annette Oxenius.

  How a single, naive T cell can give rise to diverse progenies of effector and memory cells is not completely understood. One way to achieve this is by asymmetric cell division (ACD), characterized by an unequal distribution of cellular cargo, resulting in divergent daughter cells already after the first division-one being more destined to an effector and the other more to a memory fate. Here, we established two methods to analyze the relative distribution of the older "mother" centrosome and the younger "daughter" centrosome during the first cell division of activated CD8+ T cells. We show that upon ACD, the mother centrosome is inherited by the effector-like daughter cell in a ninein-dependent mechanism. Ninein deletion abolished this effect and led to impaired differentiation of memory-like daughter cells. These findings suggest that directed centrosome inheritance upon ACD has functional effects on the fate diversification of CD8+ T cells.

Keywords:  CD8(+) T cells; CP: Immunology; asymmetric cell division; centrosome inheritance; centrosome labeling; early memory and effector cell differentiation; fate diversification of activated T cells; ninein

DOI:  https://doi.org/10.1016/j.celrep.2024.115127
Research (Wash D C). 2025 ;8 0545

Protein Phosphatase 2A Promotes CD8+ T Cell Effector Function through the Augmentation of CD28 Costimulation.

Kaixiang Zhu, Deepak Rohila, Yuanling Zhao, Dmytro Shytikov, Lize Wu, Fan Zhao, Shurong Hu, Qin Xu, Xuexiao Jin, Linrong Lu.

Protein phosphatase 2A (PP2A) is one of the most abundant serine/threonine phosphatases and plays critical roles in regulating cell fate and function. We previously showed that PP2A regulates the differentiation of CD4+ T cells and the development of thymocytes. Nevertheless, its role in CD8+ T cells remains elusive. By ablating the catalytic subunit α (Cα) of PP2A in CD8+ T cells, we revealed the essential role of PP2A in promoting the effector functions of CD8+ T cells. Notably, PP2A Cα-deficient CD8+ T cells exhibit reduced proliferation and decreased cytokine production upon stimulation in vitro. In vivo, mice lacking PP2A Cα in T cells displayed defective immune responses against lymphocytic choriomeningitis virus infection, associated with reduced CD8+ T cell expansion and decreased cytokine production. Consistently, the ablation of the PP2A Cα subunit in CD8+ T cells results in attenuated antitumor activity in mice. There is a notable decrease in the infiltration of PP2A Cα-deficient CD8+ T cells within the tumor microenvironment, and the cells that do infiltrate exhibit diminished effector functions. Mechanistically, PP2A Cα deficiency impedes CD28-induced AKT Ser473 phosphorylation, thus impairing CD8+ T cell costimulation signal. Collectively, our findings underscore the critical role of phosphatase PP2A as a propeller for CD28-mediated costimulation signaling in CD8+ T cell effector function by fine-tuning T cell activation.

DOI: https://doi.org/10.34133/research.0545
J Gastroenterol Hepatol. 2025 Jan 08.

Glucose Metabolism Reprogramming of Immune Cells in the Microenvironment of Pancreatic and Hepatobiliary Cancers.

Yongqing Zhao, Weixiong Zhu, Shi Dong, Hui Zhang, Wence Zhou.

   BACKGROUND AND AIM: Pancreatic and hepatobiliary cancers are increasing in prevalence and contribute significantly to cancer-related mortality worldwide. Emerging therapeutic approaches, particularly immunotherapy, are gaining attention for their potential to harness the patient's immune system to combat these tumors. Understanding the role of immune cells in the tumor microenvironment (TME) and their metabolic reprogramming is key to developing more effective treatment strategies. This review aims to explore the relationship between immune cell function and glucose metabolism in the TME of pancreatic and hepatobiliary cancers.
METHODS: This review synthesizes current research on the metabolic adaptations of immune cells, specifically focusing on glucose metabolism within the TME of pancreatic and hepatobiliary cancers. We examine the mechanisms by which immune cells influence tumor progression through metabolic reprogramming and how these interactions can be targeted for therapeutic purposes.
RESULTS: Immune cells in the TME undergo significant metabolic changes, with glucose metabolism playing a central role in modulating immune responses. These metabolic shifts not only affect immune cell function but also influence tumor behavior and progression. The unique metabolic features of immune cells in pancreatic and hepatobiliary cancers provide new opportunities for targeting immune responses to combat these malignancies more effectively.
CONCLUSION: Understanding the complex relationship between immune cell glucose metabolism and tumor progression in the TME of pancreatic and hepatobiliary cancers offers promising therapeutic strategies. By modulating immune responses through targeted metabolic interventions, it may be possible to improve the efficacy of immunotherapies and better combat these aggressive cancers.

Keywords:  glucose metabolism; immune cell; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1111/jgh.16873
Nature. 2025 Jan 08.

Precursors of exhausted T cells are preemptively formed in acute infection.

Talyn Chu, Ming Wu, Barbara Hoellbacher, Gustavo P de Almeida, Christine Wurmser, Jacqueline Berner, Lara V Donhauser, Gerullis Ann-Katrin, Siran Lin, J Diego Cepeda-Mayorga, Iman I Kilb, Lukas Bongers, Fabio Toppeta, Philipp Strobl, Ben Youngblood, Anna M Schulz, Alfred Zippelius, Percy A Knolle, Matthias Heinig, Carl-Philipp Hackstein, Dietmar Zehn.

T cell exhaustion limits effector T cell function in chronic infection and tumors1,2. The development of these hypofunctional T cells and of their precursors was considered to require stimulatory conditions met only upon persisting exposure to antigen and inflammation. In sharp contrast, we found similar T cell populations in the early phase of acute infections1,2. At that stage early developing TCF1+ precursor population shows an unexpected diversity, which includes precursors of normal memory T cells but also cells with a phenotype, gene-expression, and epigenetic profile that resembles precursors of exhausted T cells found in chronic infections. We demonstrate that high ligand affinity promotes, and PD-1 signaling restricts the development of these precursors. While these exhausted precursors are initially frequently found, they decline without being completely lost in infections the immune system resolves. We therefore concluded that precursor T cells with at least two distinct phenotypes are preemptively generated irrespectively of the outcome of the infection.

DOI: https://doi.org/10.1038/s41586-024-08451-4
Vaccines (Basel). 2024 Nov 23. pii: 1314. [Epub ahead of print]12(12):

Immunosenescence: Aging and Immune System Decline.

Priyanka Goyani, Rafail Christodoulou, Evros Vassiliou.

  Immunosenescence, a systematic reduction in the immune system connected with age, profoundly affects the health and well-being of elderly individuals. This review outlines the hallmark features of immunosenescence, including thymic involution, inflammaging, cellular metabolic adaptations, and hematopoietic changes, and their impact on immune cells such as macrophages, neutrophils, T cells, dendritic cells, B cells, and natural killer (NK) cells. Thymic involution impairs the immune system's capacity to react to novel antigens by reducing thymopoiesis and shifting toward memory T cells. Inflammaging, characterized by chronic systemic inflammation, further impairs immune function. Cellular metabolic adaptations and hematopoietic changes alter immune cell function, contributing to a diminished immune response. Developing ways to reduce immunosenescence and enhance immunological function in the elderly population requires an understanding of these mechanisms.

Keywords:  cytokines; immune system; immunoscenence; inflammation; thymus

DOI:  https://doi.org/10.3390/vaccines12121314
Proc Natl Acad Sci U S A. 2025 Jan 14. 122(2): e2418985122

Anti-CTLA-4 generates greater memory response than anti-PD-1 via TCF-1.

Stephen Mok, Huey Liu, Didem Ağaç Çobanoğlu, Nana-Ama A S Anang, James J Mancuso, E John Wherry, James P Allison.

  The effects of T cell differentiation arising from immune checkpoint inhibition targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on the immunological memory response remain unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T cell formation in mice reveals that memory T cells generated by anti-CTLA-4 exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more T cell factor-1 (TCF-1)+ T cells during priming, while anti-PD-1 leads to more thymocyte selection-associated high mobility group box (TOX)+ T cells. Experiments using conditional Tcf7- or Tox-knockout mice highlight that TCF-1 is essential for the memory response generated by anti-CTLA-4, whereas TOX deletion alone in T cells has no effect on the response to anti-PD-1. Deepening our understanding of how checkpoint inhibition affects memory response is crucial for advancing our understanding of the enduring impacts of these immunotherapies on the immune system.

Keywords:  anti-CTLA-4; anti-PD-1; immune checkpoint therapies; memory response

DOI:  https://doi.org/10.1073/pnas.2418985122
Mol Oncol. 2025 Jan 07.

Polyfunctional CD8+CD226+RUNX2hi effector T cells are diminished in advanced stages of chronic lymphocytic leukemia.

Maryam Rezaeifar, Shima Shahbaz, Anthea C Peters, Spencer B Gibson, Shokrollah Elahi.

  CD8+ T cells, a subset of T cells identified by the surface glycoprotein CD8, particularly those expressing the co-stimulatory molecule CD226, play a crucial role in the immune response to malignancies. However, their role in chronic lymphocytic leukemia (CLL), an immunosuppressive disease, has not yet been explored. We studied 64 CLL patients and 25 age- and sex-matched healthy controls (HCs). We analyzed the proportion of CD226-expressing cells among different CD8+ T cell subsets (including naïve, central memory, effector memory, and effectors) in CLL patients, stratified by Rai stage and immunoglobulin heavy-chain variable region gene (IgHV) mutation status. Additionally, we compared the effector functions of CD8+CD226+ cells and their CD226- counterparts. We also quantified cytokine and chemokine levels in the plasma of CLL and HCs. Furthermore, we reanalyzed the publicly available bulk RNA-seq on CD226+ and CD226-CD8+ T cells. Finally, we evaluated the impact of elevated cytokines/chemokines on CD226 expression. Our results showed that CD226-expressing cells were significantly decreased within the effector memory and effector CD8+ T cell subsets in CLL patients with advanced Rai stages and unmutated IgHV, a marker of poor prognosis. These cells displayed robust effector functions, including cytokine production, cytolytic activity, degranulation, proliferation, and migration capacity. In contrast, CD8+CD226- T cells displayed an exhausted phenotype with reduced Runt-related transcription factor 2 (RUNX2) expression. Elevated levels of interleukin-6 (IL-6) and macrophage inflammatory protein-1 beta (MIP-1β) were inversely correlated with the frequency of CD8+CD226+ T cells and may contribute to the downregulation of CD226, possibly leading to T cell dysfunction in CLL. Our findings highlight the critical role of CD8+CD226+RUNX2hi T cells in CLL and suggest that their reduction is associated with disease progression and poor clinical outcomes. This study also underscores the potential of targeting IL-6 and MIP-1β to preserve polyfunctional CD8+CD226+ T cells as a promising immunotherapy strategy.

Keywords:  CD29+ T cell; IL‐6 and MIP‐1β; NK‐T cell‐like; co‐inhibitory receptors

DOI:  https://doi.org/10.1002/1878-0261.13793
Biomaterials. 2024 Dec 27. pii: S0142-9612(24)00579-9. [Epub ahead of print]317 123043

Magnesium peroxide-based biomimetic nanoigniter degrades extracellular matrix to awake T cell-mediated cancer immunotherapy.

Huisong Hao, Shengjie Sun, Yanan Fu, Simin Wen, Yingfei Wen, Yunfei Yi, Zhangwen Peng, Yixuan Fang, Jia Tang, Tianqi Wang, Meiying Wu.

  As the elite force of our immune system, T cells play a determining role in the effectiveness of cancer immunotherapy. However, the clever tumor cells construct a strong immunosuppressive tumor microenvironment (TME) fortress to resist the attack of T cells. Herein, a magnesium peroxide (MP)-based biomimetic nanoigniter loaded with doxorubicin (DOX) and metformin (MET) is rationally designed (D/M-MP@LM) to awake T cell-mediated cancer immunotherapy via comprehensively destroying the strong TME fortress. The nanoigniter not only effectively initiate CD8+ T cell-mediated immune response by promoting the presentation of tumor antigens, but also greatly facilitate the infiltration of T cells by degrading rigid extracellular matrix (ECM). More importantly, the nanoigniter significantly augment the effector functions of infiltrated CD8+ T cells by Mg2+-mediated metalloimmunotherapy and avoid the exhaustion of CD8+ T cells by improving the acidic TME. Thus, the nanoigniter comprehensively awakes T cells and achieves remarkable tumor inhibition efficacy.

Keywords:  Biomimetic nanomedicine; Cancer therapy; Magnesium peroxide; Metalloimmunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biomaterials.2024.123043
Nature. 2025 Jan 08.

An early precursor CD8 T cell that adapts to acute or chronic viral infection.

Daniel T McManus, Rajesh M Valanparambil, Christopher B Medina, Christopher D Scharer, Donald J McGuire, Ewelina Sobierajska, Yinghong Hu, Daniel Y Chang, Andreas Wieland, Judong Lee, Tahseen H Nasti, Masao Hashimoto, James L Ross, Nataliya Prokhnevska, Maria A Cardenas, Amanda L Gill, Elisa C Clark, Kathleen Abadie, Arjun Kumar, Jonathan Kaye, Byron B Au-Yeung, Hao Yuan Kueh, Haydn T Kissick, Rafi Ahmed.

This study examines the origin and differentiation of stem-like CD8+ T cells that are essential for sustained T cell immunity in chronic viral infections and cancer and also play a key role in PD-1 directed immunotherapy1-10. These PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells, also referred to as precursors of exhausted T cells8,9, have a distinct program that allows them to adapt to chronic antigen stimulation. Using the mouse model of chronic LCMV infection we found that virus specific stem-like CD8+ T cells are generated early (day 5) during chronic infection suggesting that this crucial fate commitment occurs irrespective of infection outcome. Indeed, we found that nearly identical populations of stem-like CD8+ T cells were generated early during acute or chronic LCMV infection, and that antigen was essential for maintaining the stem-like phenotype. We next performed reciprocal adoptive transfer experiments to determine the fate of these early stem-like CD8+ T cells after viral clearance versus persistence. Following transfer of day 5 stem-like CD8+ T cells from chronically infected into acutely infected mice, these cells downregulated canonical markers of the chronic stem-like CD8+ T cells and expressed markers (CD127 and CD62L) associated with central memory CD8+ T cells. Reciprocally, when day 5 stem-like cells from acutely infected mice were transferred into chronically infected mice these CD8+ T cells functioned like chronic resource cells and responded effectively to PD-1 therapy. These findings highlight the ability of these early PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells to adapt their differentiation trajectory to either an acute or chronic viral infection. Most importantly, our study shows that the host is prepared a priori to deal with a potential chronic infection.

DOI: https://doi.org/10.1038/s41586-024-08562-y
Exp Hematol. 2025 Jan 07. pii: S0301-472X(25)00002-5. [Epub ahead of print] 104711

How age affects human hematopoietic stem and progenitor cells and strategies to mitigate HSPC aging.

Xueling Li, Jianwei Wang, Linping Hu, Tao Cheng.

Hematopoietic stem cells (HSCs) are central to blood formation and play a pivotal role in hematopoietic and systemic aging. With aging, HSCs undergo significant functional changes, such as an increased stem cell pool, declined homing and reconstitution capacity, and skewed differentiation towards myeloid and megakaryocyte/platelet progenitors. These phenotypic alterations are likely due to the expansion of certain clones, known as clonal hematopoiesis (CH), which leads to disrupted hematopoietic homeostasis, including anemia, impaired immunity, higher risks of hematological malignancies, and even associations with cardiovascular disease, highlighting the broader impact of HSC aging on overall health. HSC aging is driven by a range of mechanisms involving both intrinsic and extrinsic factors, such as DNA damage accumulation, epigenetic remodeling, inflammaging and metabolic regulation. In this review, we summarize the update understanding of age-related changes in HSPCs and the mechanisms underlie the aging process in mammalian models, especially in human study. Additionally, we provide insights into potential therapeutic strategies to counteract aging process and enhance HSC regenerative capacity, which will support therapeutic interventions and promote healthy aging.

DOI: https://doi.org/10.1016/j.exphem.2025.104711