bims-imseme 2024-12-29 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2024–12–29
twenty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Targeting P4HA1 promotes CD8+ T cell progenitor expansion toward immune memory and systemic anti-tumor immunity.
SLAMF7 defines subsets of human effector CD8 T cells.
Immunosenescence and age-related immune cells: causes of age-related diseases.
Unraveling the interplay of CD8 + T cells and microRNA signaling in cancer: implications for immune dysfunction and therapeutic approaches.
Immunometabolism in the Aging Heart.
Antigen presentation by tumor-associated macrophages drives T cells from a progenitor exhaustion state to terminal exhaustion.
HSP60 controls mitochondrial ATP generation for optimal virus-specific IL-21-producing CD4 and cytotoxic CD8 memory T cell responses.
A unique inflammaging profile generated by T cells from people with obesity is metformin resistant.
CD57+ EMRA CD8+ T cells in cancer patients over 70: associations with prior chemotherapy and response to anti-PD-1/PD-L1 therapy.
Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus.
The role of TIGIT-CD226-PVR axis in mediating T cell exhaustion and apoptosis in NSCLC.
Micro nutrients as immunomodulators in the ageing population: a focus on inflammation and autoimmunity.
Leucine zipper-based immunomagnetic purification of CAR T cells displaying multiple receptors.
Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet.
Immune imbalance in Lupus Nephritis: The intersection of T-Cell and ferroptosis.
T lymphocyte plasticity in chronic inflammatory diseases: The emerging role of the Ikaros family as a key Th17-Treg switch.
PD-1-Enhanced Treg Cell Senescence in Advanced Maternal Age.
Targeting T cell exhaustion: emerging strategies in non-small cell lung cancer.
Effects of Aging on Glucose and Lipid Metabolism in Mice.
The interplay of NAD and hypoxic stress and its relevance for ageing.

Cancer Cell. 2024 Dec 23. pii: S1535-6108(24)00476-8. [Epub ahead of print]

Targeting P4HA1 promotes CD8+ T cell progenitor expansion toward immune memory and systemic anti-tumor immunity.

Shijun Ma, Li-Teng Ong, Zemin Jiang, Wee Chyan Lee, Puay Leng Lee, Mubaraka Yusuf, Henrik J Ditzel, Yulan Wang, Qingfeng Chen, Wenyu Wang, Xiaojian Wu, Ern Yu Tan, Qiang Yu.

  Successful immunotherapy relies on both intratumoral and systemic immunity, which is yet to be achieved for most patients with cancer. Here, we identify P4HA1, encoding prolyl 4-hydroxylase 1, as a crucial regulator of CD8+ T cell differentiation strongly upregulated in tumor-draining lymph nodes (TDLNs) and hypoxic tumor microenvironment. P4HA1 accumulates in mitochondria, disrupting the tricarboxylic acid (TCA) cycle through aberrant α-ketoglutarate and succinate metabolism, promoting mitochondria unfitness and exhaustion while suppressing progenitor expansion. Targeting P4HA1 enhances both adoptive and endogenous TCF1+ CD8+ T progenitor expansion while mitigating the development of exhaustion in the tumor, TDLN, and blood, enabling a notable and durable systemic anti-cancer immunity. We propose that P4HA1 induction in CD8+ T cells in cancer orchestrates an immune-escape program, offering a T cell-directed target for system immunotherapy in solid tumors.

Keywords:  CAR T cells; P4HA1; PD-1; T cell exhaustion; T cell memory; cancer immunotherapy; hypoxia; mitochondria; solid tumors; systemic immunity

DOI:  https://doi.org/10.1016/j.ccell.2024.12.001
Sci Rep. 2024 Dec 28. 14(1): 30779

SLAMF7 defines subsets of human effector CD8 T cells.

Hassen Kared, Crystal Tan, Vipin Narang, Shu Wen Tan, Chin Hui Xian, Alicia Tay Seok Wei, Josephine Lum, Ezequiel Ruiz-Mateos, Reena Rajasuriar, Adeeba Kamarulzaman, Tze Pin Ng, Anis Larbi.

Long-term control of viral replication relies on the efficient differentiation of memory T cells into effector T cells during secondary immune responses. Recent findings have identified T cell precursors for both memory and exhausted T cells, suggesting the existence of progenitor-like effector T cells. These cells can persist without antigenic challenge but expand and acquire effector functions upon recall immune responses. In this study, we demonstrate that the combination of SLAMF7 with either CD27 or TCF-1 effectively identifies progenitor-like effector CD8 T cells, while SLAMF7 with GPR56 or TOX defines effector CD8 T cells. These markers allow for the clear segregation of these distinct cell subsets. SLAMF7+ CD8T cells are dynamically modulated during viral infections, including HIV, HCV, CMV, and SARS-CoV-2, as well as during aging. We further characterize the SLAMF7 signature at both phenotypic and transcriptional levels. Notably, during aging, the SLAMF7 pathway becomes dysregulated, resulting in persistent phosphorylation of STAT1. Additionally, SLAMF7 ligation in the presence of IL-15 induces TCF-1 expression, which promotes the homeostatic proliferation of progenitor-like effector CD8 T cells.

DOI: https://doi.org/10.1038/s41598-024-80971-5
Arch Pharm Res. 2024 Dec 26.

Immunosenescence and age-related immune cells: causes of age-related diseases.

Nam-Hee Kim, So-Jin Sim, Hong-Gyu Han, Jeong-Hyuk Yoon, Yong-Hyun Han.

  Immunosenescence is a weakening of the immune system due to aging, characterized by changes in immune cells and dysregulated immune function. Age-related immune cells are increasing with aging. They are associated with chronic prolonged inflammation, causing tissue dysfunction and age-related diseases. Here, we discuss increased pro-inflammatory activity of aged macrophages, accumulation of lymphocytes with an age-associated phenotype, and specific alterations in both functions and characteristics of these immune cells. These cellular changes are associated with development of age-related diseases. Additionally, we reviewed various therapeutic strategies targeting age-related immunosenescence, providing pathways to mitigate effects of age-related diseases.

Keywords:  Age-related diseases; Aging; Immune cell; Immunosenescence

DOI:  https://doi.org/10.1007/s12272-024-01529-7
J Transl Med. 2024 Dec 20. 22(1): 1131

Unraveling the interplay of CD8 + T cells and microRNA signaling in cancer: implications for immune dysfunction and therapeutic approaches.

Arefeh Zabeti Touchaei, Sogand Vahidi.

  MicroRNAs (miRNAs) emerge as critical regulators of CD8 + T cell function within the complex tumor microenvironment (TME). This review explores the multifaceted interplay between miRNAs and CD8 + T cells across various cancers. We discuss how specific miRNAs influence CD8 + T cell activation, recruitment, infiltration, and effector function. Dysregulation of these miRNAs can contribute to CD8 + T cell exhaustion and immune evasion, hindering anti-tumor immunity. Conversely, manipulating miRNA expression holds promise for enhancing CD8 + T cell activity and improving cancer immunotherapy outcomes. We delve into the role of miRNAs in CD8 + T-cell function across different cancer types, including gliomas, gastric and colon cancer, oral squamous cell carcinoma, thyroid carcinoma, lymphomas, melanoma, breast cancer, renal cell carcinoma, ovarian cancer, uterine corpus endometrial cancer, bladder cancer, acute myeloid leukemia, chronic myelogenous leukemia, and osteosarcoma. Additionally, we explore how extracellular vesicles and cytokines modulate CD8 + T-cell function through complex interactions with miRNAs. Finally, we discuss the potential impact of radiotherapy and specific drugs on miRNA expression and CD8 + T-cell activity within the TME. This review highlights the immense potential of targeting miRNAs to manipulate CD8 + T-cell activity for the development of novel and improved cancer immunotherapies.

Keywords:  CD8 + T-cells; Cancer; Cytokines; Drug therapy; Extracellular vesicles; MicroRNAs (miRNAs); Radiotherapy; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s12967-024-05963-5
J Am Heart Assoc. 2024 Dec 24. e039216

Immunometabolism in the Aging Heart.

Kranti A Mapuskar, Barry London, Zeb R Zacharias, Jon C D Houtman, Bryan G Allen.

  Structural, functional, and molecular-level changes in the aging heart are influenced by a dynamic interplay between immune signaling and cellular metabolism that is referred to as immunometabolism. This review explores the crosstalk between cellular metabolic pathways including glycolysis, oxidative phosphorylation, fatty acid metabolism, and the immune processes that govern cardiac aging. With a rapidly aging population that coincides with increased cardiovascular risk and cancer incidence rates, understanding the immunometabolic underpinnings of cardiac aging provides a foundation for identifying therapeutic targets to mitigate cardiac dysfunction. Aging alters the immune environment of the heart by concomitantly driving the changes in immune cell metabolism, mitochondrial dysfunction, and redox signaling. Shifts in these metabolic pathways exacerbate inflammation and impair tissue repair, creating a vicious cycle that accelerates cardiac functional decline. Treatment with cancer therapy further complicates this landscape, as aging-associated immunometabolic disruptions augment the susceptibility to cardiotoxicity. The current review highlights therapeutic strategies that target the immunometabolic axis to alleviate cardiac aging pathologies. Interventions include modulating metabolic intermediates, improving mitochondrial function, and leveraging immune signaling pathways to restore cardiac health. Advances in immunometabolism thus hold significant potential for translating preclinical findings into therapies that improve the quality of life for the aging population and underscore the need for approaches that address the immunometabolic mechanisms of cardiac aging, providing a framework for future research.

Keywords:  cardiac aging; immunometabolism; inflammaging; oxidative phosphorylation

DOI:  https://doi.org/10.1161/JAHA.124.039216
Immunity. 2024 Dec 19. pii: S1074-7613(24)00541-7. [Epub ahead of print]

Antigen presentation by tumor-associated macrophages drives T cells from a progenitor exhaustion state to terminal exhaustion.

Jessica Waibl Polania, Alexandra Hoyt-Miggelbrink, William H Tomaszewski, Lucas P Wachsmuth, Selena J Lorrey, Daniel S Wilkinson, Emily Lerner, Karolina Woroniecka, John B Finlay, Katayoun Ayasoufi, Peter E Fecci.

  Whereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor-exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single-cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAMs)-not tumor cells-were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to αPD1 immunotherapy. Thus, targeting TAM-T cell interactions may further license checkpoint blockade responses.

Keywords:  T cell exhaustion; brain metastasis; brain tumor; glioblastoma; immunotherapy; tumor immunology; tumor microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.immuni.2024.11.026
Commun Biol. 2024 Dec 21. 7(1): 1688

HSP60 controls mitochondrial ATP generation for optimal virus-specific IL-21-producing CD4 and cytotoxic CD8 memory T cell responses.

Nazanin Ghahari, Saina Shegefti, Mahsa Alaei, Amine Amara, Roman Telittchenko, Stéphane Isnard, Jean-Pierre Routy, David Olagnier, Julien van Grevenynghe.

We have shown that virus-specific CD4 and CD8 memory T cells (TM) induce autophagy after T cell receptor (TCR) engagement to provide free glutamine and fatty acids, including in people living with HIV-1 (PLWH). These nutrients fuel mitochondrial ATP generation through glutaminolysis and fatty acid oxidation (FAO) pathways, to fulfill the bioenergetic demands for optimal IL-21 and cytotoxic molecule production in CD4 and CD8 cells, respectively. Here, we expand our knowledge on how the metabolic events that occur in the mitochondria of virus-specific TM down-stream of the autophagy are regulated. We show that HSP60 chaperone positively regulates the protein levels for multiple glutaminolysis- and FAO-related enzymes, thereby actively fueling the levels of cellular alpha-ketoglutarate (αKG) and related mitochondrial ATP-dependent antiviral T cell immunity in both CD4 and CD8 TM. Finally, we provide a way to rescue defective ATP generation in mitochondria and dependent effector functions in virus-specific TM including anti-HIV-1 protective responses, when HSP60 expression is impaired after TCR engagement in patients, in the form of dimethyl 2-oxoglutarate (DMKG) supplementation.

DOI: https://doi.org/10.1038/s42003-024-07326-8
Geroscience. 2024 Dec 21.

A unique inflammaging profile generated by T cells from people with obesity is metformin resistant.

S SantaCruz-Calvo, S Saraswat, G H Kalantar, E Zukowski, H Marszalkowski, A Javidan, F Gholamrezaeinejad, L P Bharath, P A Kern, X D Zhang, B S Nikolajczyk.

  The alarmingly high prevalence of obesity in older adults coupled with the negative health effects of chronic inflammation in both obesity and aging highlight the importance of studies investigating the impacts of obesity on age-related inflammation. Since shifts in peripheral T-cell metabolism and function drive systemic inflammation in both obesity and aging, we hypothesize that obesity impacts the Th17-dominated inflammaging profile we identified in lean subjects and thus modifies the anti-inflammatory effects of geroprotective drugs like metformin. New cytokine profiling data showed that CD4+ T cells from older people with obesity generate a profile that specifically excludes Th17 cytokines. Metformin failed to change the age-associated T-cell profile in obesity, despite lowering both mitochondrial respiration and reactive oxygen species (ROS) production. Metformin did not improve macroautophagy in T cells from older people with obesity, in sharp contrast to the ability of metformin to promote autophagy in T cells from older lean subjects. These data indicate that body mass index modifies the mechanisms supporting inflammaging in T cells from older subjects, and that metformin-mediated restoration of redox balance is insufficient to stem obesity-associated inflammaging. We conclude that obesity fundamentally changes the mechanisms that promote inflammaging, and thus obesity becomes a critical consideration for clinical trials of geroprotective agents such as metformin.

Keywords:  Age-related inflammation; Autophagy; Partial least squares discriminant analysis; Redox balance; Systemic inflammation

DOI:  https://doi.org/10.1007/s11357-024-01441-4
Immun Ageing. 2024 Dec 27. 21(1): 89

CD57+ EMRA CD8+ T cells in cancer patients over 70: associations with prior chemotherapy and response to anti-PD-1/PD-L1 therapy.

Cécile Gonnin, Michelle Leemans, Florence Canoui-Poitrine, Morgane Lebraud, Aurélien Corneau, Louise Roquebert, Philippe Caillet, Pierre Gay, Johanna Canovas, Axelle Histe, Catherine Blanc, Carine El-Sissy, Anis Larbi, Johanne Poisson, Pauline Ober, Pascaline Boudou-Rouquette, Pierre-André Natella, Hélène Vallet, Besma Saadaoui, Richard Layese, Eric Tartour, Elena Paillaud, Clémence Granier.

   BACKGROUND: Immune ageing complicates cancer treatment in older individuals. While immunotherapy targeting the PD-1/PD-L1 pathway can reinvigorate T cells, these cells tend to become senescent with age. This study investigates different CD8+ T cell subsets usually associated with senescence, in cancer patients over 70 years old who are undergoing anti-PD-1/PD-L1 immunotherapy, and examines the relationship between these senescent cells and prior chemotherapy exposure. We analyzed data from the Elderly Cancer Patient (ELCAPA) cohort, which included 35 patients enrolled between March 2018 and March 2021.
RESULTS: Flow cytometry and unsupervised analysis were employed to characterize Effector Memory CD45RA+ (EMRA) and CD8+ T cell senescence at baseline, before initiating PD-1/PD-L1 therapy. EMRA cells were found to overexpress CD57 and KLRG1 compared to overall CD8+ T cells. Chemotherapy prior to anti-PD-1/PD-L1 was associated with an increased proportion of CD57+ EMRA CD8+ T cells (p = 0.009) and its granzyme B (GRZB) subset (p = 0.007). Using a 10% cut-off to define positivity, the six-month non-response tends to be associated with the CD57+ GRZB+ EMRA positivity (p = 0.097). Other CD8+ T cell subsets (EMRA, CD57+, or KLRG1+), usually associated with senescence, showed no significant association with previous chemotherapy or response to anti-PD-1/anti-PD-L1 therapy.
CONCLUSIONS: These findings underscore the impact of prior chemotherapy on expanding the pool of senescent T cells, particularly CD57+ EMRA CD8+ T and CD57+ GRZB+ EMRA CD8+ T cells, whose expansion could potentially affect the effectiveness of anti-PD-1/PD-L1 immunotherapy in elderly patients. This highlights the need for tailored approaches in this population.

Keywords:  Ageing; CD57; CD8-positive T-lymphocytes; Cancer; EMRA; Geriatrics; Immune-ageing; Immunotherapy; PD-1; Senescence; Tumour

DOI:  https://doi.org/10.1186/s12979-024-00487-4
Clin Exp Immunol. 2024 Dec 25. pii: uxae127. [Epub ahead of print]

Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus.

Anna Radziszewska, Hannah Peckham, Restuadi Restuadi, Melissa Kartawinata, Dale Moulding, Nina M de Gruijter, George A Robinson, Maryam Butt, Claire T Deakin, Meredyth G Ll Wilkinson, Lucy R Wedderburn, Elizabeth C Jury, Elizabeth C Rosser, Coziana Ciurtin.

  Juvenile systemic lupus erythematosus (JSLE) is an autoimmune condition which causes significant morbidity in children and young adults and is more severe in its presentation than adult-onset SLE. While many aspects of immune dysfunction have been studied extensively in adult-onset SLE, there is limited and contradictory evidence of how cytotoxic CD8+ T cells contribute to disease pathogenesis and studies exploring cytotoxicity in JSLE are virtually non-existent. Here, we report that CD8+ T cell cytotoxic capacity is reduced in JSLE versus healthy controls, irrespective of treatment or disease activity. Transcriptomic and serum metabolomic analysis identified that this reduction in cytotoxic CD8+ T cells in JSLE was associated with upregulated type I interferon (IFN) signalling, mitochondrial dysfunction, and metabolic disturbances when compared to controls. Greater interrogation of the influence of these pathways on altered cytotoxic CD8+ T cell function demonstrated that JSLE CD8+ T cells had enlarged mitochondria and enhanced sensitivity to IFN-α leading to selective apoptosis of effector memory (EM) CD8+ T cells, which are enriched for cytotoxic mediator-expressing cells. This process ultimately contributes to the observed reduction in CD8+ T cell cytotoxicity in JSLE, reinforcing the growing evidence that mitochondrial dysfunction is a key pathogenic factor affecting multiple immune cell populations in type I IFN-driven rheumatic diseases.

Keywords:  CD8+ T cells; cytotoxicity; interferon; juvenile systemic lupus erythematosus

DOI:  https://doi.org/10.1093/cei/uxae127
Apoptosis. 2024 Dec 26.

The role of TIGIT-CD226-PVR axis in mediating T cell exhaustion and apoptosis in NSCLC.

Liang Qian, Ling Wu, Xiaohui Miao, Jiao Xu, Yao Zhou.

  The treatment of non-small cell lung cancer (NSCLC) remains a critical challenge in oncology, primarily due to the dysfunction and exhaustion of T cells within the tumor microenvironment, which greatly limits the effectiveness of immunotherapy. This study investigates the regulatory role of the T cell immunoglobulin and ITIM domain (TIGIT)-CD226-PVR signaling axis in the exhaustion and apoptosis of cluster of differentiation (CD)27+/CD127+T cells in NSCLC. Utilizing single-cell sequencing technology, we conducted a comprehensive gene expression analysis of T cells in a mouse model of NSCLC. Bioinformatics analysis revealed that the TIGIT-CD226-PVR signaling axis is highly active in the CD27+/CD127+T cell subset and is closely associated with their functional decline and exhaustion. In vitro experiments further demonstrated that inhibiting the TIGIT-PVR pathway while activating the CD226-PVR pathway significantly restored T cell proliferation and effector function. Importantly, in vivo studies showed that targeting this axis can significantly alleviate T cell exhaustion, enhance their cytotoxicity against NSCLC cells, and promote apoptosis, thereby improving the efficacy of immunotherapy.

Keywords:  CD27+/CD127+T cells; Immunotherapy; Non-small cell lung cancer; Single-cell sequencing; T cell exhaustion; TIGIT-CD226-PVR axis

DOI:  https://doi.org/10.1007/s10495-024-02052-2
Immun Ageing. 2024 Dec 27. 21(1): 88

Micro nutrients as immunomodulators in the ageing population: a focus on inflammation and autoimmunity.

Bhavani Sowndharya Balamurugan, Mathan Muthu Chinnakannu Marimuthu, Vickram Agaram Sundaram, Bharath Saravanan, Prasanth Chandrababu, Hitesh Chopra, Tabarak Malik.

  Immunosenescence, the slow degradation of immune function over time that is a hallmark and driver of aging, makes older people much more likely to be killed by common infections (such as flu) than young adults, but it also contributes greatly to rates of chronic inflammation in later life. Such micro nutrients are crucial for modulating effective immune responses and their deficiencies have been associated with dysfunctional immunity in the elderly. In this review, we specifically focused on the contribution of major micro nutrients (Vitamins A, D and E, Vitamin C; Zinc and Selenium) as immunomodulators in ageing population especially related to inflame-ageing process including autoimmunity. This review will cover these hologenomic interactions, including how micro nutrients can modulate immune cell function and/or cytokine production to benefit their hosts with healthy mucous-associated immunity along with a sustainable immunologic homeostasis. For example, it points out the modulatory effects of vitamin D on both innate and adaptive immunity, with a specific focus on its ability to suppress pro-inflammatory cytokines synthesis while enhancing regulatory T-cell function. In the same context, also zinc is described as important nutrient for thymic function and T-cell differentiation but exhibits immunomodulatory functions by decreasing inflammation. In addition, the review will go over how micro nutrient deficiencies increase systemic chronic low-grade inflammation and, inflammaging as well as actually enhance autoimmune pathologies in old age. It assesses the potential role of additional targeted nutritional supplementation with micro nutrients to counteract these effects, promoting wider immune resilience in older adults. This review collates the current evidence and highlights the role of adequate micro nutrient intake on inflammation and autoimmunity during ageing, providing plausible origins for nutritional interventions to promote healthy immune aging.

Keywords:  Ageing population; Autoimmunity; Immune modulation; Immunosenescence; Inflammation; Micronutrients

DOI:  https://doi.org/10.1186/s12979-024-00492-7
Nat Biomed Eng. 2024 Dec;8(12): 1592-1614

Leucine zipper-based immunomagnetic purification of CAR T cells displaying multiple receptors.

Scott E James, Sophia Chen, Brandon D Ng, Jacob S Fischman, Lorenz Jahn, Alexander P Boardman, Adhithi Rajagopalan, Harold K Elias, Alyssa Massa, Dylan Manuele, Katherine B Nichols, Amina Lazrak, Nicole Lee, Aoife M Roche, Alexander G McFarland, Angelina Petrichenko, John K Everett, Frederic D Bushman, Teng Fei, Anastasia I Kousa, Andri L Lemarquis, Susan DeWolf, Jonathan U Peled, Santosha A Vardhana, Christopher A Klebanoff, Marcel R M van den Brink.

Resistance to chimaeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms, most notably antigen loss and tumour-induced immune suppression. It has been suggested that T cells expressing multiple CARs may overcome the resistance of tumours and that T cells expressing receptors that switch inhibitory immune-checkpoint signals into costimulatory signals may enhance the activity of the T cells in the tumour microenvironment. However, engineering multiple features into a single T cell product is difficult because of the transgene-packaging constraints of current gene-delivery vectors. Here we describe a cell-sorting method that leverages leucine zippers for the selective single-step immunomagnetic purification of cells co-transduced with two vectors. Such 'Zip sorting' facilitated the generation of T cells simultaneously expressing up to four CARs and coexpressing up to three 'switch' receptors. In syngeneic mouse models, T cells with multiple CARs and multiple switch receptors eliminated antigenically heterogeneous populations of leukaemia cells coexpressing multiple inhibitory ligands. By combining diverse therapeutic strategies, Zip-sorted multi-CAR multi-switch-receptor T cells can overcome multiple mechanisms of CAR T cell resistance.

DOI: https://doi.org/10.1038/s41551-024-01287-3
Cell Stem Cell. 2024 Dec 12. pii: S1934-5909(24)00413-2. [Epub ahead of print]

Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet.

Salma Merchant, Animesh Paul, Amanda Reyes, Daniel Cassidy, Ashley Leach, Dohun Kim, Sarah Muh, Gerik Grabowski, Gerta Hoxhaj, Zhiyu Zhao, Sean J Morrison.

  Fatty acid oxidation is of uncertain importance in most stem cells. We show by 14C-palmitate tracing and metabolomic analysis that hematopoietic stem/progenitor cells (HSPCs) engage in long-chain fatty acid oxidation that depends upon carnitine palmitoyltransferase 1a (CPT1a) and hydroxyacyl-CoA dehydrogenase (HADHA) enzymes. CPT1a or HADHA deficiency had little or no effect on HSPCs or hematopoiesis in young adult mice. Young HSPCs had the plasticity to oxidize other substrates, including glutamine, and compensated for loss of fatty acid oxidation by decreasing pyruvate dehydrogenase phosphorylation, which should increase function. This metabolic plasticity declined as mice aged, when CPT1a or HADHA deficiency altered hematopoiesis and impaired hematopoietic stem cell (HSC) function upon serial transplantation. A high-fat diet increased fatty acid oxidation and reduced HSC function. This was rescued by CPT1a or HADHA deficiency, demonstrating that increased fatty acid oxidation can undermine HSC function. Long-chain fatty acid oxidation is thus dispensable in young HSCs but necessary during aging and deleterious with a high-fat diet.

Keywords:  aging; fatty acid; hematopoiesis; high-fat diet; metabolic plasticity; metabolism; mitochondria; β-oxidation

DOI:  https://doi.org/10.1016/j.stem.2024.11.014
Front Immunol. 2024 ;15 1520570

Immune imbalance in Lupus Nephritis: The intersection of T-Cell and ferroptosis.

Yunhe Fan, Kuai Ma, Yumeng Lin, Junyi Ren, Haoyu Peng, Lan Yuan, Moussa Ide Nasser, Xuan Jiang, Ke Wang.

  Ferroptosis is a novel form of cell death characterized by unlimited accumulation of iron-dependent lipid peroxides. It is often accompanied by disease, and the relationship between ferroptosis of immune cells and immune regulation has been attracting increasing attention. Initially, it was found in cancer research that the inhibition of regulatory T cell (Treg) ferroptosis and the promotion of CD8+ T cell ferroptosis jointly promoted the formation of an immune-tolerant environment in tumors. T-cell ferroptosis has subsequently been found to have immunoregulatory effects in other diseases. As an autoimmune disease characterized by immune imbalance, T-cell ferroptosis has attracted attention for its potential in regulating immune balance in lupus nephritis. This article reviews the metabolic processes within different T-cell subsets in lupus nephritis (LN), including T follicular helper (TFH) cells, T helper (Th)17 cells, Th1 cells, Th2 cells, and Treg cells, and reveals that these cellular metabolisms not only facilitate the formation of a T-cell immune imbalance but are also closely associated with the occurrence of ferroptosis. Consequently, we hypothesize that targeting the metabolic pathways of ferroptosis could become a novel research direction for effectively treating the immune imbalance in lupus nephritis by altering T-cell differentiation and the incidence of ferroptosis.

Keywords:  Lupus Nephritis; T cells; cellular metabolism; ferroptosis; immune imbalance

DOI:  https://doi.org/10.3389/fimmu.2024.1520570
Autoimmun Rev. 2024 Dec 22. pii: S1568-9972(24)00226-X. [Epub ahead of print] 103735

T lymphocyte plasticity in chronic inflammatory diseases: The emerging role of the Ikaros family as a key Th17-Treg switch.

A Ramón-Vázquez, P Flood, T L Cashman, P Patil, S Ghosh.

  T helper (Th) 17 and regulatory T (Treg) cells are highly plastic CD4+ Th cell subsets, being able not only to actively adapt to their microenvironment, but also to interconvert, acquiring mixed identity markers. These phenotypic changes are underpinned by transcriptional control mechanisms, chromatin reorganization events and epigenetic modifications, that can be hereditable and stable over time. The Ikaros family of transcription factors have a predominant role in T cell subset specification through mechanisms of transcriptional program regulation that enable phenotypical diversification. They are crucial factors in maintaining Th17/Treg balance and therefore, homeostatic conditions in the tissues. However, they are also implicated in pathogenic processes, where their transcriptional repression contributes to the control of autoimmune processes. In this review, we discuss how T cell fate, specifically in humans, is regulated by the Ikaros family and its interplay with additional factors like the Notch signaling pathway, gut microbiota and myeloid-T cell interactions. Further, we highlight how the transcriptional activity of the Ikaros family impacts the course of T cell mediated chronic inflammatory diseases like rheumatoid and psoriatic arthritis, inflammatory bowel disease, systemic lupus erythematosus and multiple sclerosis. We conclude by discussing recently developed therapeutics designed to target Ikaros family members.

Keywords:  Chronic inflammatory diseases; Ikaros family; T cell differentiation; T cell plasticity; Transcriptional control

DOI:  https://doi.org/10.1016/j.autrev.2024.103735
Adv Sci (Weinh). 2024 Dec 23. e2411613

PD-1-Enhanced Treg Cell Senescence in Advanced Maternal Age.

Guang-Shun Gong, Yu-Jing Zhang, Xiao-Hui Hu, Xin-Xiu Lin, Ai-Hua Liao.

  Senescence occurs earlier in the immune system than in solid organs as age increases. Regulatory T (Treg) cells are among the first cells to exhibit signs of aging. However, whether advanced-age pregnancy involves Treg cell aging remains unclear. This study demonstrated that the aging of women is accompanied by aging Treg cells and that PD-1 regulates Treg cell aging. The transfer of young Treg cells can improve the pregnancy outcomes of reproductive-aged mice by reducing the level of IFN-γ, a proinflammatory cytokine secreted by Treg cells in aged mice. Transferring α-PD-1 mAb-treated aged Treg cells increases the level of IL-10, an anti-inflammatory cytokine secreted by Treg cells in reproductive-aged mice. Collectively, these findings suggest a potential therapeutic strategy for preventing adverse pregnancy outcomes in older women.

Keywords:  adoptive transfer; advance maternal age; cell senescence; maternal‐fetal interface; mice; programmed cell death protein 1; regulatory T cell; senescence‐associated secretory phenotype

DOI:  https://doi.org/10.1002/advs.202411613
Front Immunol. 2024 ;15 1507501

Targeting T cell exhaustion: emerging strategies in non-small cell lung cancer.

Xianqiang Liu, Xiaowei Xi, Shengshan Xu, Hongyu Chu, Penghui Hu, Dong Li, Bin Zhang, Hejie Liu, Tianxiao Jiang, Zhuming Lu.

  Lung cancer continues to be a major contributor to cancer-related deaths globally. Recent advances in immunotherapy have introduced promising treatments targeting T cell functionality. Central to the efficacy of these therapies is the role of T cells, which are often rendered dysfunctional due to continuous antigenic stimulation in the tumor microenvironment-a condition referred to as T cell exhaustion. This review addresses the critical challenge of T cell exhaustion in non-small cell lung cancer (NSCLC), offering a detailed examination of its molecular underpinnings and the resultant therapeutic ineffectiveness. We synthesize current knowledge on the drivers of T cell exhaustion, evaluate emerging strategies for its reversal, and explore the potential impact of these insights for enhancing the clinical efficacy of immunotherapies. By consolidating reported clinical trials and preclinical studies, this article highlights innovative approaches to modulate immune responses and improve patient outcomes, thus providing a roadmap for future research and therapeutic development in lung cancer immunotherapy.

Keywords:  T cell exhaustion; cytokines; immune checkpoint inhibitors; immunotherapy; non-small cell lung cancer

DOI:  https://doi.org/10.3389/fimmu.2024.1507501
Aging Cell. 2024 Dec 27. e14462

Effects of Aging on Glucose and Lipid Metabolism in Mice.

Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.

  Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.

Keywords:  NAD; aging; metabolic rate; mice

DOI:  https://doi.org/10.1111/acel.14462
Ageing Res Rev. 2024 Dec 20. pii: S1568-1637(24)00464-1. [Epub ahead of print]104 102646

The interplay of NAD and hypoxic stress and its relevance for ageing.

Johannes Burtscher, Vanna Denti, Johanna M Gostner, Alexander Kh Weiss, Barbara Strasser, Katharina Hüfner, Martin Burtscher, Giuseppe Paglia, Martin Kopp, Tobias Dünnwald.

  Nicotinamide adenine dinucleotide (NAD) is an essential regulator of cellular metabolism and redox processes. NAD levels and the dynamics of NAD metabolism change with increasing age but can be modulated via the diet or medication. Because NAD metabolism is complex and its regulation still insufficiently understood, achieving specific outcomes without perturbing delicate balances through targeted pharmacological interventions remains challenging. NAD metabolism is also highly sensitive to environmental conditions and can be influenced behaviorally, e.g., by exercise. Changes in oxygen availability directly and indirectly affect NAD levels and may result from exposure to ambient hypoxia, increased oxygen demand during exercise, ageing or disease. Cellular responses to hypoxic stress involve rapid alterations in NAD metabolism and depend on many factors, including age, glucose status, the dose of the hypoxic stress and occurrence of reoxygenation phases, and exhibit complex time-courses. Here we summarize the known determinants of NAD-regulation by hypoxia and evaluate the role of NAD in hypoxic stress. We define the specific NAD responses to hypoxia and identify a great potential of the modulation of NAD metabolism regarding hypoxic injuries. In conclusion, NAD metabolism and cellular hypoxia responses are strongly intertwined and together mediate protective processes against hypoxic insults. Their interactions likely contribute to age-related changes and vulnerabilities. Targeting NAD homeostasis presents a promising avenue to prevent/treat hypoxic insults and - conversely - controlled hypoxia is a potential tool to regulate NAD homeostasis.

Keywords:  ageing; hypoxia inducible factor; hypoxic injury; nicotinamide adenine dinucleotide; oxygen; sirtuins

DOI:  https://doi.org/10.1016/j.arr.2024.102646