bims-imseme 2024-06-02 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2024–06–02
twelve papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Rapid metabolic regulation of a novel arginine methylation of KCa3.1 attenuates T cell exhaustion.
Antitumor progenitor exhausted CD8+ T cells are sustained by TCR engagement.
13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.
The roles of essential trace elements in T cell biology.
Targeting metabolism to enhance immunotherapy within tumor microenvironment.
T cell-intrinsic PKD3 fine-tunes differentiation into CD8+ central memory T cells and CD8 single positive thymocyte development.
Ablation of Atp5if1 impairs metabolic reprogramming and proliferation of T lymphocytes and compromises mouse survival.
Targeting senescent cells to reshape the tumor microenvironment and improve anticancer efficacy.
Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models.
Nanowires engineer naive T cells for immunotherapy.
Memory CD8 T cells are vulnerable to chronic IFN-γ signals but not to CD4 T cell deficiency in MHCII-deficient mice.
Adipocyte-specific inactivation of NAMPT, a key NAD+ biosynthetic enzyme, causes a metabolically-unhealthy lean phenotype in female mice during aging.

bioRxiv. 2024 May 14. pii: 2024.05.09.593421. [Epub ahead of print]

Rapid metabolic regulation of a novel arginine methylation of KCa3.1 attenuates T cell exhaustion.

Piyush Sharma, Ao Guo, Suresh Poudel, Emilio Boada-Romero, Katherine C Verbist, Gustavo Palacios, Kalyan Immadisetty, Mark J Chen, Dalia Haydar, Ashutosh Mishra, Junmin Peng, M Madan Babu, Giedre Krenciute, Evan S Glazer, Douglas R Green.

T cell exhaustion is linked to persistent antigen exposure and perturbed activation events, correlating with poor disease prognosis. Tumor-mediated T cell exhaustion is well documented; however, how the nutrient-deprived tumor niche affects T cell receptor (TCR) activation is largely unclear. We show that methionine metabolism licenses optimal TCR signaling by regulating the protein arginine methylome, and limiting methionine availability during early TCR signaling promotes subsequent T cell exhaustion. We discovered a novel arginine methylation of a Ca 2+ -activated potassium transporter, KCa3.1, prevention of which results in increased Ca 2+ -mediated NFAT1 activation, NFAT1 promoter occupancy, and T cell exhaustion. Furthermore, methionine supplementation reduces nuclear NFAT1 in tumor-infiltrating T cells and augments their anti-tumor activity. These findings demonstrate metabolic regulation of T cell exhaustion determined during TCR engagement.

DOI: https://doi.org/10.1101/2024.05.09.593421
Nat Immunol. 2024 May 30.

Antitumor progenitor exhausted CD8+ T cells are sustained by TCR engagement.

Xin Lan, Tian Mi, Shanta Alli, Cliff Guy, Mohamed Nadhir Djekidel, Xueyan Liu, Shannon Boi, Partha Chowdhury, Minghong He, Dietmar Zehn, Yongqiang Feng, Ben Youngblood.

The durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8+ T cells (Tpex). Tpex serve as a resource for replenishing effector T cells and preserve their quantity through self-renewal. However, it is unknown how T cell receptor (TCR) engagement affects the self-renewal capacity of Tpex in settings of continued antigen exposure. Here we use a Lewis lung carcinoma model that elicits either optimal or attenuated TCR signaling in CD8+ T cells to show that formation of Tpex in tumor-draining lymph nodes and their intratumoral persistence is dependent on optimal TCR engagement. Notably, attenuated TCR stimulation accelerates the terminal differentiation of optimally primed Tpex. This TCR-reinforced Tpex development and self-renewal is coupled to proximal positioning to dendritic cells and epigenetic imprinting involving increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, this study highlights the critical function of TCR engagement in sustaining Tpex during tumor progression.

DOI: https://doi.org/10.1038/s41590-024-01843-8
Sci Adv. 2024 May 31. 10(22): eadj1431

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.

Eric H Ma, Michael S Dahabieh, Lisa M DeCamp, Irem Kaymak, Susan M Kitchen-Goosen, Brandon M Oswald, Joseph Longo, Dominic G Roy, Mark J Verway, Radia M Johnson, Bozena Samborska, Lauren R Duimstra, Catherine A Scullion, Mya Steadman, Matthew Vos, Thomas P Roddy, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.

Infusion of 13C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes-infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.

DOI: https://doi.org/10.1126/sciadv.adj1431
J Cell Mol Med. 2024 May;28(10): e18390

The roles of essential trace elements in T cell biology.

Linbo Lan, Zhao Feng, Xiaobin Liu, Baojun Zhang.

  T cells are crucial for adaptive immunity to regulate proper immune response and immune homeostasis. T cell development occurs in the thymus and mainly differentiates into CD4+ and CD8+ T cell subsets. Upon stimulation, naive T cells differentiate into distinct CD4+ helper and CD8+ cytotoxic T cells, which mediate immunity homeostasis and defend against pathogens or tumours. Trace elements are minimal yet essential components of human body that cannot be overlooked, and they participate in enzyme activation, DNA synthesis, antioxidant defence, hormone production, etc. Moreover, trace elements are particularly involved in immune regulations. Here, we have summarized the roles of eight essential trace elements (iron, zinc, selenium, copper, iodine, chromium, molybdenum, cobalt) in T cell development, activation and differentiation, and immune response, which provides significant insights into developing novel approaches to modulate immunoregulation and immunotherapy.

Keywords:  T cells; immune regulation; minerals; nutrients; trace elements

DOI:  https://doi.org/10.1111/jcmm.18390
Acta Pharmacol Sin. 2024 May 29.

Targeting metabolism to enhance immunotherapy within tumor microenvironment.

Xiao-Hui Liang, Xin-Yi Chen, Yue Yan, Ao-Yu Cheng, Jia-Yi Lin, Yi-Xin Jiang, Hong-Zhuan Chen, Jin-Mei Jin, Xin Luan.

  Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Like cancer cells, immune cells within the tumor microenvironment or premetastatic niche also undergo extensive metabolic reprogramming, which profoundly impacts anti-tumor immune responses. Numerous evidence has illuminated that immunosuppressive TME and the metabolites released by tumor cells, including lactic acid, Prostaglandin E2 (PGE2), fatty acids (FAs), cholesterol, D-2-Hydroxyglutaric acid (2-HG), adenosine (ADO), and kynurenine (KYN) can contribute to CD8+ T cell dysfunction. Dynamic alterations of these metabolites between tumor cells and immune cells can similarly initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response. This review summarizes the new landscape beyond the classical metabolic pathways in tumor cells, highlighting the pivotal role of metabolic disturbance in the immunosuppressive microenvironment, especially how nutrient deprivation in TME leads to metabolic reprogramming of CD8+ T cells. Likewise, it emphasizes the current therapeutic targets or strategies related to tumor metabolism and immune response, providing therapeutic benefits for tumor immunotherapy and drug development in the future. Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Dynamic alterations of metabolites between tumor cells and immune cells initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response.

Keywords:  dynamic interplay; immune response; metabolic reprogramming; targeted strategies; tumor microenvironment

DOI:  https://doi.org/10.1038/s41401-024-01304-w
Immunology. 2024 May 26.

T cell-intrinsic PKD3 fine-tunes differentiation into CD8+ central memory T cells and CD8 single positive thymocyte development.

Jiří Koutník, Sebastian Peer, Dominik Humer, Grzegorz Sumara, Michael Leitges, Gottfried Baier, Kerstin Siegmund.

  Members of the Protein kinases D (PKD) family are described as regulators of T cell responses. From the two T cell-expressed isoforms PKD2 and PKD3, so far mainly the former was thoroughly investigated and is well understood. Recently, we have investigated also PKD3 using conventional as well as conditional T cell-specific knockout models. These studies suggested PKD3 to be a T cell-extrinsic regulator of the cells' fate. However, these former model systems did not take into account possible redundancies with the highly homologous PKD2. To overcome this issue and thus properly unravel PKD3's T cell-intrinsic functions, here we additionally used a mouse model overexpressing a constitutively active isoform of PKD3 specifically in the T cell compartment. These transgenic mice showed a slightly higher proportion of central memory T cells in secondary lymphoid organs and blood. This effect could not be explained via differences upon polyclonal stimulation in vitro, however, may be connected to the observed developmental aberrances in the CD8 single positive compartment during thymic development. Lastly, the observed alterations in the CD8+ T cell compartment did not impact proper immune response upon immunization with ovalbumin or in a subcutaneous tumour model suggesting only a small to absent biological relevance. Taking together the knowledge of all our published studies on PKD3 in the T cell compartment, we now conclude that T cell-intrinsic PKD3 is a fine-tuner of central memory T cell as well as CD8 single positive thymocyte development.

Keywords:  CD8 cells; T cells; protein kinases/phosphatases; thymic

DOI:  https://doi.org/10.1111/imm.13804
iScience. 2024 Jun 21. 27(6): 109863

Ablation of Atp5if1 impairs metabolic reprogramming and proliferation of T lymphocytes and compromises mouse survival.

Inés Romero-Carramiñana, Sonia Dominguez-Zorita, Pau B Esparza-Moltó, José M Cuezva.

  T cells experience metabolic reprogramming to an enhanced glycolysis upon activation. Herein, we have investigated whether ATPase Inhibitory Factor 1 (IF1), the physiological inhibitor of mitochondrial ATP synthase, participates in rewiring T cells to a particular metabolic phenotype. We show that the activation of naive CD4+ T lymphocytes both in vitro and in vivo is accompanied by a sharp upregulation of IF1, which is expressed only in Th1 effector cells. T lymphocytes of conditional CD4+-IF1-knockout mice display impaired glucose uptake and flux through glycolysis, reducing the biogenesis of mitochondria and cellular proliferation after activation. Consequently, mice devoid of IF1 in T lymphocytes cannot mount an effective Th1 response against bacterial infection compromising their survival. Overall, we show that the inhibition of a fraction of ATP synthase by IF1 regulates metabolic reprogramming and functionality of T cells, highlighting the essential role of IF1 in adaptive immune responses.

Keywords:  Biological sciences; Immunology; Molecular biology; Physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109863
Semin Cancer Biol. 2024 May 27. pii: S1044-579X(24)00036-1. [Epub ahead of print]

Targeting senescent cells to reshape the tumor microenvironment and improve anticancer efficacy.

Birong Jiang, Wei Zhang, Xuguang Zhang, Yu Sun.

  Cancer is daunting pathology with remarkable breadth and scope, spanning genetics, epigenetics, proteomics, metalobomics and cell biology. Cellular senescence represents a stress-induced and essentially irreversible cell fate associated with aging and various age-related diseases, including malignancies. Senescent cells are characterized of morphologic alterations and metabolic reprogramming, and develop a highly active secretome termed as the senescence-associated secretory phenotype (SASP). Since the first discovery, senescence has been understood as an important barrier to tumor progression, as its induction in pre-neoplastic cells limits carcinogenesis. Paradoxically, senescent cells arising in the tumor microenvironment (TME) contribute to tumor progression, including augmented therapeutic resistance. In this article, we define typical forms of senescent cells commonly observed within the TME and how senescent cells functionally remodel their surrounding niche, affect immune responses and promote cancer evolution. Furthermore, we highlight the recently emerging pipelines of senotherapies particularly senolytics, which can selectively deplete senescent cells from affected organs in vivo and impede tumor progression by restoring therapeutic responses and securing anticancer efficacies. Together, co-targeting cancer cells and their normal but senescent counterparts in the TME holds the potential to achieve increased therapeutic benefits and restrained disease relapse in future clinical oncology.

Keywords:  senescence-associated secretory phenotype; senescent cell; senolytics; senotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2024.05.002
Cell Death Dis. 2024 May 31. 15(5): 382

Targeting the autophagy-NAD axis protects against cell death in Niemann-Pick type C1 disease models.

Tetsushi Kataura, Lucia Sedlackova, Congxin Sun, Gamze Kocak, Niall Wilson, Peter Banks, Faisal Hayat, Sergey Trushin, Eugenia Trushina, Oliver D K Maddocks, John E Oblong, Satomi Miwa, Masaya Imoto, Shinji Saiki, Daniel Erskine, Marie E Migaud, Sovan Sarkar, Viktor I Korolchuk.

Impairment of autophagy leads to an accumulation of misfolded proteins and damaged organelles and has been implicated in plethora of human diseases. Loss of autophagy in actively respiring cells has also been shown to trigger metabolic collapse mediated by the depletion of nicotinamide adenine dinucleotide (NAD) pools, resulting in cell death. Here we found that the deficit in the autophagy-NAD axis underpins the loss of viability in cell models of a neurodegenerative lysosomal storage disorder, Niemann-Pick type C1 (NPC1) disease. Defective autophagic flux in NPC1 cells resulted in mitochondrial dysfunction due to impairment of mitophagy, leading to the depletion of both the reduced and oxidised forms of NAD as identified via metabolic profiling. Consequently, exhaustion of the NAD pools triggered mitochondrial depolarisation and apoptotic cell death. Our chemical screening identified two FDA-approved drugs, celecoxib and memantine, as autophagy activators which effectively restored autophagic flux, NAD levels, and cell viability of NPC1 cells. Of biomedical relevance, either pharmacological rescue of the autophagy deficiency or NAD precursor supplementation restored NAD levels and improved the viability of NPC1 patient fibroblasts and induced pluripotent stem cell (iPSC)-derived cortical neurons. Together, our findings identify the autophagy-NAD axis as a mechanism of cell death and a target for therapeutic interventions in NPC1 disease, with a potential relevance to other neurodegenerative disorders.

DOI: https://doi.org/10.1038/s41419-024-06770-y
Nat Nanotechnol. 2024 May 27.

Nanowires engineer naive T cells for immunotherapy.

Dragana Slavkovic-Lukic, Luca Gattinoni.

DOI: https://doi.org/10.1038/s41565-024-01651-z
Nat Commun. 2024 May 28. 15(1): 4418

Memory CD8 T cells are vulnerable to chronic IFN-γ signals but not to CD4 T cell deficiency in MHCII-deficient mice.

Ruka Setoguchi, Tomoya Sengiku, Hiroki Kono, Eiryo Kawakami, Masato Kubo, Tadashi Yamamoto, Shohei Hori.

The mechanisms by which the number of memory CD8 T cells is stably maintained remains incompletely understood. It has been postulated that maintaining them requires help from CD4 T cells, because adoptively transferred memory CD8 T cells persist poorly in MHC class II (MHCII)-deficient mice. Here we show that chronic interferon-γ signals, not CD4 T cell-deficiency, are responsible for their attrition in MHCII-deficient environments. Excess IFN-γ is produced primarily by endogenous colonic CD8 T cells in MHCII-deficient mice. IFN-γ neutralization restores the number of memory CD8 T cells in MHCII-deficient mice, whereas repeated IFN-γ administration or transduction of a gain-of-function STAT1 mutant reduces their number in wild-type mice. CD127high memory cells proliferate actively in response to IFN-γ signals, but are more susceptible to attrition than CD127low terminally differentiated effector memory cells. Furthermore, single-cell RNA-sequencing of memory CD8 T cells reveals proliferating cells that resemble short-lived, terminal effector cells and documents global downregulation of gene signatures of long-lived memory cells in MHCII-deficient environments. We propose that chronic IFN-γ signals deplete memory CD8 T cells by compromising their long-term survival and by diverting self-renewing CD127high cells toward terminal differentiation.

DOI: https://doi.org/10.1038/s41467-024-48704-4
Am J Physiol Endocrinol Metab. 2024 May 29.

Adipocyte-specific inactivation of NAMPT, a key NAD+ biosynthetic enzyme, causes a metabolically-unhealthy lean phenotype in female mice during aging.

Nathan Qi, Michael P Franczyk, Shintaro Yamaguchi, Daiki Kojima, Kaori Hayashi, Akiko Satoh, Noboru Ogiso, Takeshi Kanda, Yo Sasaki, Brian N Finck, Brian J DeBosch, Jun Yoshino.

  Nicotinamide adenine dinucleotide (NAD+) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD+ metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD+ biosynthesis, mediated by a rate-limiting NAD+ biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole-body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (≤ 4-month-old), middle aged (10 to 14-month-old), and old (≥ 18-month-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic euglycemic clamp procedure demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPARγ) in an age-dependent manner. In addition, administration of a PPARγ agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD+-PPARγ axis in maintaining functional integrity and quantity of adipose tissue, and whole-body metabolic function in female mice during aging.

Keywords:  Adipose tissue; NAD; PPARγ; aging; insulin resistance

DOI:  https://doi.org/10.1152/ajpendo.00313.2023