bims-imseme 2024-08-04 papers

Issue of 2024‒08‒04
five papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Autoimmun Rev. 2024 Jul 29. pii: S1568-9972(24)00074-0. [Epub ahead of print] 103583

Remodeling of T-cell mitochondrial metabolism to treat autoimmune diseases.

Liyan Lin, Ruyu Ren, Qiao Xiong, Chunfu Zheng, Bin Yang, Huiqing Wang.

T cells are key drivers of the pathogenesis of autoimmune diseases by producing cytokines, stimulating the generation of autoantibodies, and mediating tissue and cell damage. Distinct mitochondrial metabolic pathways govern the direction of T-cell differentiation and function and rely on specific nutrients and metabolic enzymes. Metabolic substrate uptake and mitochondrial metabolism form the foundational elements for T-cell activation, proliferation, differentiation, and effector function, contributing to the dynamic interplay between immunological signals and mitochondrial metabolism in coordinating adaptive immunity. Perturbations in substrate availability and enzyme activity may impair T-cell immunosuppressive function, fostering autoreactive responses and disrupting immune homeostasis, ultimately contributing to autoimmune disease pathogenesis. A growing body of studies has explored how metabolic processes regulate the function of diverse T-cell subsets in autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), autoimmune hepatitis (AIH), inflammatory bowel disease (IBD), and psoriasis. This review describes the coordination of T-cell biology by mitochondrial metabolism, including the electron transport chain (ETC), oxidative phosphorylation, amino acid metabolism, fatty acid metabolism, and one‑carbon metabolism. This study elucidated the intricate crosstalk between mitochondrial metabolic programs, signal transduction pathways, and transcription factors. This review summarizes potential therapeutic targets for T-cell mitochondrial metabolism and signaling in autoimmune diseases, providing insights for future studies.

Keywords: Autoimmune diseases; Fatty acid metabolism; Mitochondrial metabolism; OXPHOS; Regulatory T cells; T helper cells; Treatment

DOI: https://doi.org/10.1016/j.autrev.2024.103583

Eur J Immunol. 2024 Jul 28. e2451080

PP2A catalytic subunit alpha is critically required for CD8+ T-cell homeostasis and antibacterial responses.

Xian Zhou, Meilu Li, Minji Ai, Yanfeng Li, Xingxing Zhu, Michael J Hansen, Jun Zhong, Kenneth L Johnson, Roman Zenka, Akhilesh Pandey, Larry R Pease, Hu Zeng.

Although the functions of tyrosine phosphatases in T-cell biology have been extensively studied, our knowledge on the contribution of serine/threonine phosphatases in T cells remains poor. Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine phosphatases. It is important in thymocyte development and CD4+ T-cell differentiation. Utilizing a genetic model in which its catalytic subunit alpha isoform (PP2A Cα) is deleted in T cells, we investigated its contribution to CD8+ T-cell homeostasis and effector functions. Our results demonstrate that T-cell intrinsic PP2A Cα is critically required for CD8+ T-cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A Cα-deficient CD8+ T cells exhibit reduced proliferation and survival. CD8+ T-cell antibacterial response is strictly dependent on PP2A Cα. Expression of Bcl2 transgene rescues CD8+ T-cell homeostasis in spleens, but not in intestinal mucosal site, nor does it restore defective antibacterial responses. Finally, proteomics and phosphoproteomics analyses reveal potential targets dependent on PP2A Cα, including mTORC1 and AKT. Thus, PP2A Cα is a key modulator of CD8+ T-cell homeostasis and effector functions.

Keywords: Apoptosis; Bacterial infections; CD8 T cells; Intestinal immunity; PP2A

DOI: https://doi.org/10.1002/eji.202451080

Semin Hematol. 2024 Jul 06. pii: S0037-1963(24)00082-9. [Epub ahead of print]

Tuning CAR T-cell therapies for efficacy and reduced toxicity.

Danielle Blud, Patricia Rubio-Reyes, Rachel Perret, Robert Weinkove.

Chimeric antigen receptor (CAR) T-cell therapies are a standard of care for certain relapsed or refractory B-cell cancers. However, many patients do not respond to CAR T-cell therapy or relapse later, short- and long-term toxicities are common, and current CAR T-cell therapies have limited efficacy for solid cancers. The gene engineering inherent in CAR T-cell manufacture offers an unprecedented opportunity to control cellular characteristics and design products that may overcome these limitations. This review summarises available methods to "tune" CAR T-cells for optimal efficacy and safety. The components of a typical CAR, and the modifications that can influence CAR T-cell function are discussed. Methods of engineering passive, inducible or autonomous control mechanisms into CAR T-cells, allowing selective limitation or enhancement of CAR T-cell activity are reviewed. The impact of manufacturing processes on CAR T-cell function are considered, including methods of limiting CAR T-cell terminal differentiation and exhaustion, and the use of specific T-cell subsets as the CAR T starting material. We discuss the use of multicistronic transgenes and multiplexed gene editing. Finally, we highlight the need for innovative clinical trial designs if we are to make the most of the opportunities offered by CAR T-cell therapies.

Keywords: Adverse Drug Reaction; CAR T-cell Therapy; Chimeric Antigen Receptors; Genetic Engineering; Single-chain Variable Fragments; Treatment Efficacy

DOI: https://doi.org/10.1053/j.seminhematol.2024.07.003

Mech Ageing Dev. 2024 Jul 30. pii: S0047-6374(24)00075-7. [Epub ahead of print] 111975

The emerging importance of lymphangiogenesis in aging and aging-associated diseases.

Rui-Cheng Ji.

Lymphatic aging represented by cellular and functional changes, is involved in increased geriatric disorders, but the intersection between aging and lymphatic modulation is less clear. Lymphatic vessels play an essential role in maintaining tissue fluid homeostasis, regulating immune function, and promoting macromolecular transport. Lymphangiogenesis and lymphatic remodeling following cellular senescence and organ deterioration are crosslinked with the progression of some lymphatic-associated diseases, e.g., atherosclerosis, inflammation, lymphoedema, and cancer. Age-related detrimental tissue changes may occur in lymphatic vessels with diverse etiologies, and gradually shift towards chronic low-grade inflammation, so-called inflammaging, and lead to decreased immune response. The investigation of the relationship between advanced age and organ deterioration is becoming an area of rapidly increasing significance in lymphatic biology and medicine. Here we highlight the emerging importance of lymphangiogenesis and lymphatic remodeling in the regulation of aging-related pathological processes, which will help to find new avenues for effective intervention to promote healthy aging.

Keywords: Aging; Lymphangiogenesis; Lymphatic-associated diseases; Macrophage; Senescence-associated secretory phenotype (SASP); VEGF-C/VEGFR-3

DOI: https://doi.org/10.1016/j.mad.2024.111975

ACS Nano. 2024 Jul 31.

A Nanocapsule System Combats Aging by Inhibiting Age-Related Angiogenesis Deficiency and Glucolipid Metabolism Disorders.

Bo Li, Qiang Zhang, Jiahui Cheng, Yanfei Feng, Lixian Jiang, Xinxin Zhao, Yang Lv, Kun Yang, Jiaran Shi, Wei Wei, Peng Guo, Jun Wang, Mengqiu Cao, Weina Ding, Ji Wang, Diansan Su, Yan Zhou, Rifeng Gao.

Insufficient angiogenic stimulation and dysregulated glycolipid metabolism in senescent vascular endothelial cells (VECs) constitute crucial features of vascular aging. Concomitantly, the generation of excess senescence-associated secretory phenotype (SASP) and active immune-inflammatory responses propagates within injured vessels, tissues, and organs. Until now, targeted therapies that efficiently rectify phenotypic abnormalities in senescent VECs have still been lacking. Here, we constructed a Pd/hCeO2-BMS309403@platelet membrane (PCBP) nanoheterostructured capsule system loaded with fatty acid-binding protein 4 (FABP4) inhibitors and modified with platelet membranes and investigated its therapeutic role in aged mice. PCBP showed significant maintenance in aged organs and demonstrated excellent biocompatibility. Through cyclic tail vein administration, PCBP extended the lifespan and steadily ameliorated abnormal phenotypes in aged mice, including SASP production, immune and inflammatory status, and age-related metabolic disorders. In senescent ECs, PCBP mediated the activation of vascular endothelial growth factor (VEGF) signaling and glycolysis and inhibition of FABP4 by inducing the synthesis of hypoxia-inducible factor-1α, thereby reawakening neovascularization and restoring glycolipid metabolic homeostasis. In conclusion, the PCBP nanocapsule system provides a promising avenue for interventions against aging-induced dysfunction.

Keywords: SASP; aging; angiogenesis; glucolipid metabolism; heterostructures

DOI: https://doi.org/10.1021/acsnano.4c02269