bims-imseme 2022-09-18 papers

Issue of 2022‒09‒18
eight papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

Immunology. 2022 Sep 11.

Metabolic plasticity and regulation of T cell exhaustion.

Fei Li, Huiling Liu, Dan Zhang, Yanlin Ma, Bingdong Zhu.

The metabolic reprogramming during T cell activation and differentiation affects T cell fate and immune responses. Cell metabolism may serve as the driving force that induces epigenetic modifications, contributing to regulating T cell differentiation. Persistent pathogen infection leads to T cell exhaustion, which is composed of two main subsets and with distinct metabolic characteristics. The progenitor exhausted T cells utilize mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) for energy, while terminally exhausted T cells mainly rely on glycolytic metabolism with impaired glycolysis and OXPHOS. Here, we compiled the latest research on how T cell metabolism defines differentiation, focusing on T cell exhaustion during chronic infections. In addition, metabolic-related factors including antigen stimulation signals strength, cytokines and epigenetics affecting T cell exhaustion were also reviewed. Furthermore, the intervention strategies on metabolism and epigenetics to reverse T cell exhaustion were discussed in detail, which may contribute to achieving the goal of prevention and treatment of T cell exhaustion.

Keywords: Chronic infection; Epigenetics; Glycolysis; T cell exhaustion; T cell metabolism

DOI: https://doi.org/10.1111/imm.13575

J Cancer Res Clin Oncol. 2022 Sep 15.

Novel targets for immunotherapy associated with exhausted CD8 + T cells in cancer.

Lulu Zhang, Bo Zhang, Lin Li, Yingchun Ye, Yuchuan Wu, Qing Yuan, Wenfeng Xu, Xue Wen, Xiyuan Guo, Siji Nian.

In response to prolonged stimulation by tumour antigens, T cells gradually become exhausted. There is growing evidence that exhausted T cells not only lose their potent effector functions but also express multiple inhibitory receptors. Checkpoint blockade (CPB) therapy can improve cancer by reactivating exhausted effector cell function, leading to durable clinical responses, but further improvements are needed given the limited number of patients who benefit from treatment, even with autoimmune complications. Here, we suggest, based on recent advances that tumour antigens are the primary culprits of exhaustion, followed by some immune cells and cytokines that also play an accomplice role in the exhaustion process, and we also propose that chronic stress-induced hypoxia and hormones also play an important role in promoting T-cell exhaustion. Understanding the classification of exhausted CD8+ T-cell subpopulations and their functions is important for the effectiveness of immune checkpoint blockade therapies. We mapped the differentiation of T-cell exhausted subpopulations by changes in transcription factors, indicating that T-cell exhaustion is a dynamic developmental process. Finally, we summarized the novel immune checkpoints associated with depletion in recent years and combined them with bioinformatics to construct a web of exhaustion-related immune checkpoints with the aim of finding novel therapeutic targets associated with T-cell exhaustion in malignant tumours, aiming to revive the killing ability of exhausted T cells and restore anti-tumour immunity through combined targeted immunotherapy.

Keywords: Cancers; Inhibitory receptors; NRP1; PD-1; PTPN6; SIGLEC15; T-cell exhaustion

DOI: https://doi.org/10.1007/s00432-022-04326-1

Nat Cell Biol. 2022 Sep 15.

An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory.

Alessio Lanna, Bruno Vaz, Clara D'Ambra, Salvatore Valvo, Claudia Vuotto, Valerio Chiurchiù, Oliver Devine, Massimo Sanchez, Giovanna Borsellino, Arne N Akbar, Marco De Bardi, Derek W Gilroy, Michael L Dustin, Brendan Blumer, Michael Karin.

The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse. Telomere vesicles retained the Rad51 recombination factor that enabled telomere fusion with T-cell chromosome ends lengthening them by an average of ~3,000 base pairs. Thus, there are antigen-specific populations of T cells whose ageing fate decisions are based on telomere vesicle transfer upon initial contact with APCs. These telomere-acquiring T cells are protected from senescence before clonal division begins, conferring long-lasting immune protection.

DOI: https://doi.org/10.1038/s41556-022-00991-z

Front Aging. 2022 ;3 999299

Editorial: Insights in aging and the immune system: 2021.

Laura Haynes, Leena P Bharath.

Keywords: T cells; aging; autoimmune disease; inflammation; senescence

DOI: https://doi.org/10.3389/fragi.2022.999299

Lancet Healthy Longev. 2022 Jan;pii: S2666-7568(21)00300-7. [Epub ahead of print]3(1): e67-e77

The costs and benefits of senotherapeutics for human health.

Marco Raffaele, Manlio Vinciguerra.

Cellular senescence is a major contributor to age-related diseases in humans; however, it also has a beneficial role in physiological and pathological processes, including wound healing, host immunity, and tumour suppression. Reducing the burden of cell senescence in animal models of cardiometabolic disorders, inflammatory conditions, neurodegenerative diseases, and cancer using pharmaceutical approaches that selectively target senescent cells (ie, senolytics) or that suppress senescence-associated secretory phenotype (ie, senomorphics) holds great promise for the management of chronic age-associated conditions. Although studies have provided evidence that senolytics or senomorphics are effective at decreasing the number of senescent cells in humans, the short-term and long-term side-effects of these therapies are largely unknown. In this Review, we systematically discuss the senolytics and senomorphics that have been investigated in clinical trials or have been used off-label, presenting their various adverse effects. Despite the potential of senotherapeutics to transform anti-ageing medicine, a cautionary approach regarding unwanted dose-dependent side-effects should be adopted.

DOI: https://doi.org/10.1016/S2666-7568(21)00300-7

Aging Cell. 2022 Sep 11. e13710

The emergent role of mitochondrial surveillance in cellular health.

Elissa Tjahjono, Daniel R Kirienko, Natalia V Kirienko.

Mitochondrial dysfunction is one of the primary causatives for many pathologies, including neurodegenerative diseases, cancer, metabolic disorders, and aging. Decline in mitochondrial functions leads to the loss of proteostasis, accumulation of ROS, and mitochondrial DNA damage, which further exacerbates mitochondrial deterioration in a vicious cycle. Surveillance mechanisms, in which mitochondrial functions are closely monitored for any sign of perturbations, exist to anticipate possible havoc within these multifunctional organelles with primitive origin. Various indicators of unhealthy mitochondria, including halted protein import, dissipated membrane potential, and increased loads of oxidative damage, are on the top of the lists for close monitoring. Recent research also indicates a possibility of reductive stress being monitored as part of a mitochondrial surveillance program. Upon detection of mitochondrial stress, multiple mitochondrial stress-responsive pathways are activated to promote the transcription of numerous nuclear genes to ameliorate mitochondrial damage and restore compromised cellular functions. Co-expression occurs through functionalization of transcription factors, allowing their binding to promoter elements to initiate transcription of target genes. This review provides a comprehensive summary of the intricacy of mitochondrial surveillance programs and highlights their roles in our cellular life. Ultimately, a better understanding of these surveillance mechanisms is expected to improve healthspan.

Keywords: aging; mitochondria; mitochondrial membrane transport proteins; mitophagy; physiological stress; reactive oxygen species; surveillance

DOI: https://doi.org/10.1111/acel.13710