bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–02–25
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Insulin and IGF-1 have both overlapping and distinct effects on CD4+ T cell mitochondria, metabolism, and function.
  2. FGF21 suppresses CD8+ T cell antitumour activity.
  3. Magnesium and the Hallmarks of Aging.
  4. PP2A catalytic subunit alpha is critically required for CD8 + T cell homeostasis and anti-bacterial responses.
  5. Enhanced Branched-Chain Amino Acid Metabolism Improves Age-Related Reproduction in C. elegans.
  6. Tumor-Associated Monocytes Reprogram CD8+ T Cells into Central Memory-Like Cells with Potent Antitumor Effects.
  7. The gene regulatory basis of bystander activation in CD8+ T cells.
  8. Scd-1 deficiency promotes the differentiation of CD8+ T effector.
  9. A versatile CRISPR-Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells.
  10. Metabolic engineering for optimized CAR-T cell therapy.
  11. Bridging the gender gap in autoimmunity with T-cell-targeted biomaterials.
  12. Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment.
  13. Discovering the strength of immunometabolism in cancer therapy: Employing metabolic pathways to enhance immune responses.
  14. Mitochondria-Targeted Catalase Does Not Suppress Development of Cellular Senescence during Aging.
  15. Intermittent fasting promotes rejuvenation of immunosenescent phenotypes in aged adipose tissue.
  16. IL-10 constrains sphingolipid metabolism to limit inflammation.
  17. An angel or a devil? Current view on the role of CD8+ T cells in the pathogenesis of myasthenia gravis.
  18. Author Correction: Senolytic CAR T cells reverse senescence-associated pathologies.
  19. The significance of targeting lysosomes in cancer immunotherapy.
  1. Sci Rep. 2024 02 21. 14(1): 4331
    Insulin and IGF-1 have both overlapping and distinct effects on CD4+ T cell mitochondria, metabolism, and function.
    Kaitlin Kiernan, Yazan Alwarawrah, Amanda G Nichols, Keiko Danzaki, Nancie J MacIver.
      Insulin and insulin-like growth factor 1 (IGF-1) are metabolic hormones with known effects on CD4+ T cells through insulin receptor (IR) and IGF-1 receptor (IGF-1R) signaling. Here, we describe specific and distinct roles for these hormones and receptors. We have found that IGF-1R, but not IR, expression is increased following CD4+ T cell activation or following differentiation toward Th17 cells. Although both insulin and IGF-1 increase the metabolism of CD4+ T cells, insulin has a more potent effect. However, IGF-1 has a unique role and acts specifically on Th17 cells to increase IL-17 production and Th17 cell metabolism. Furthermore, IGF-1 decreases mitochondrial membrane potential and mitochondrial reactive oxygen species (mROS) in Th17 cells, providing a cytoprotective effect. Interestingly, both IR and IGF-1R are required for this effect of IGF-1 on mitochondria, which suggests that the hybrid IR/IGF-1R may be required for mediating the effect of IGF-1 on mitochondrial membrane potential and mROS production.
    DOI:  https://doi.org/10.1038/s41598-024-54836-w
  2. Nat Rev Endocrinol. 2024 Feb 20.
    FGF21 suppresses CD8+ T cell antitumour activity.
    Olivia Tysoe.
      
    DOI:  https://doi.org/10.1038/s41574-024-00964-2
  3. Nutrients. 2024 Feb 09. pii: 496. [Epub ahead of print]16(4):
    Magnesium and the Hallmarks of Aging.
    Ligia J Dominguez, Nicola Veronese, Mario Barbagallo.
      Magnesium is an essential ion in the human body that regulates numerous physiological and pathological processes. Magnesium deficiency is very common in old age. Age-related chronic diseases and the aging process itself are frequently associated with low-grade chronic inflammation, called 'inflammaging'. Because chronic magnesium insufficiency has been linked to excessive generation of inflammatory markers and free radicals, inducing a chronic inflammatory state, we formerly hypothesized that magnesium inadequacy may be considered among the intermediaries helping us explain the link between inflammaging and aging-associated diseases. We show in this review evidence of the relationship of magnesium with all the hallmarks of aging (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, disabled autophagy, dysbiosis, and chronic inflammation), which may positively affect the human healthspan. It is feasible to hypothesize that maintaining an optimal balance of magnesium during one's life course may turn out to be a safe and economical strategy contributing to the promotion of healthy aging. Future well-designed studies are necessary to further explore this hypothesis.
    Keywords:  aging; frailty; hallmarks of aging; healthy aging; magnesium; multimorbidity
    DOI:  https://doi.org/10.3390/nu16040496
  4. bioRxiv. 2024 Feb 09. pii: 2024.02.06.578745. [Epub ahead of print]
    PP2A catalytic subunit alpha is critically required for CD8 + T cell homeostasis and anti-bacterial 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.
      While 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 anti-bacterial 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 the defective anti-bacterial 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.
    DOI:  https://doi.org/10.1101/2024.02.06.578745
  5. bioRxiv. 2024 Feb 09. pii: 2023.02.09.527915. [Epub ahead of print]
    Enhanced Branched-Chain Amino Acid Metabolism Improves Age-Related Reproduction in C. elegans.
    Chen Lesnik, Rachel Kaletsky, Jasmine M Ashraf, Salman Sohrabi, Vanessa Cota, Titas Sengupta, William Keyes, Shijing Luo, Coleen T Murphy.
      Reproductive aging is one of the earliest human aging phenotypes, and mitochondrial dysfunction has been linked to oocyte quality decline. However, it is not known which mitochondrial metabolic processes are critical for oocyte quality maintenance with age. To understand how mitochondrial processes contribute to C. elegans oocyte quality, we characterized the mitochondrial proteomes of young and aged wild-type and long-reproductive daf-2 mutants. Here we show that the mitochondrial proteomic profiles of young wild-type and daf-2 worms are similar and share upregulation of branched-chain amino acid (BCAA) metabolism pathway enzymes. Reduction of the BCAA catabolism enzyme BCAT-1 shortens reproduction, elevates mitochondrial reactive oxygen species levels, and shifts mitochondrial localization. Moreover, bcat-1 knockdown decreases oocyte quality in daf-2 worms and reduces reproductive capability, indicating the role of this pathway in the maintenance of oocyte quality with age. Importantly, oocyte quality deterioration can be delayed, and reproduction can be extended in wild-type animals both by bcat-1 overexpression and by supplementing with Vitamin B1, a cofactor needed for BCAA metabolism.
    DOI:  https://doi.org/10.1101/2023.02.09.527915
  6. Adv Sci (Weinh). 2024 Feb 22. e2304501
    Tumor-Associated Monocytes Reprogram CD8+ T Cells into Central Memory-Like Cells with Potent Antitumor Effects.
    Zeliang Yang, Liang Liu, Zhenyu Zhu, Zixi Hu, Bowen Liu, Jingjing Gong, Yuan Jin, Juan Luo, Yichen Deng, Yan Jin, Guangxi Wang, Yuxin Yin.
      CD8+ T cells are critical for host antitumor responses, whereas persistent antigenic stimulation and excessive inflammatory signals lead to T cell dysfunction or exhaustion. Increasing early memory T cells can improve T cell persistence and empower T cell-mediated tumor eradication, especially for adoptive cancer immunotherapy. Here, it is reported that tumor-associated monocytes (TAMos) are highly correlated with the accumulation of CD8+ memory T cells in human cancers. Further analysis identifies that TAMos selectively reprogram CD8+ T cells into T central memory-like (TCM -like) cells with enhanced recall responses. L-NMMA, a pan nitric oxide synthase inhibitor, can mitigate TAMo-mediated inhibition of T cell proliferation without affecting TCM -like cell generation. Moreover, the modified T cells by TAMo exposure and L-NMMA treatment exhibit long-term persistence and elicit superior antitumor effects in vivo. Mechanistically, the transmembrane protein CD300LG is involved in TAMo-mediated TCM -like cell polarization in a cell-cell contact-dependent manner. Thus, the terminally differentiated TAMo subset (CD300LGhigh ACElow ) mainly contributes to TCM -like cell development. Taken together, these findings establish the significance of TAMos in boosting T-cell antitumor immunity.
    Keywords:  CD300LG; T cell exhaustion; T central memory-like cells; nitric oxide synthase; tumor-associated monocytes (TAMos)
    DOI:  https://doi.org/10.1002/advs.202304501
  7. Sci Immunol. 2024 Feb 23. 9(92): eadf8776
    The gene regulatory basis of bystander activation in CD8+ T cells.
    Neva B Watson, Ravi K Patel, Connor Kean, Janelle Veazey, Oyebola O Oyesola, Nathan Laniewski, Jennifer K Grenier, Jocelyn Wang, Cybelle Tabilas, Kristel J Yee Mon, Adrian J McNairn, Seth A Peng, Samantha P Wesnak, Kito Nzingha, Miles P Davenport, Elia D Tait Wojno, Kristin M Scheible, Norah L Smith, Andrew Grimson, Brian D Rudd.
      CD8+ T cells are classically recognized as adaptive lymphocytes based on their ability to recognize specific foreign antigens and mount memory responses. However, recent studies indicate that some antigen-inexperienced CD8+ T cells can respond to innate cytokines alone in the absence of cognate T cell receptor stimulation, a phenomenon referred to as bystander activation. Here, we demonstrate that neonatal CD8+ T cells undergo a robust and diverse program of bystander activation, which corresponds to enhanced innate-like protection against unrelated pathogens. Using a multi-omics approach, we found that the ability of neonatal CD8+ T cells to respond to innate cytokines derives from their capacity to undergo rapid chromatin remodeling, resulting in the usage of a distinct set of enhancers and transcription factors typically found in innate-like T cells. We observed that the switch between innate and adaptive functions in the CD8+ T cell compartment is mediated by changes in the abundance of distinct subsets of cells. The innate CD8+ T cell subset that predominates in early life was also present in adult mice and humans. Our findings provide support for the layered immune hypothesis and indicate that the CD8+ T cell compartment is more functionally diverse than previously thought.
    DOI:  https://doi.org/10.1126/sciimmunol.adf8776
  8. Front Cell Infect Microbiol. 2024 ;14 1325390
    Scd-1 deficiency promotes the differentiation of CD8+ T effector.
    Yiwei Lin, Xushuo Li, Haojie Shan, Jie Gao, Yanying Yang, Linlan Jiang, Lu Sun, Yuwen Chen, Fangming Liu, Xiaowei Yu.
      The impact of various fatty acid types on adaptive immunity remains uncertain, and their roles remain unelucidated. Stearoyl-CoA desaturase (Scd) is a Δ-9 desaturase, which is a key rate-limiting enzyme for the conversion of saturated fatty acids (SFA) to monounsaturated fatty acids (MUFA) in the fatty acid de novo synthesis. Scd-1 converts stearic acid (SA) and palmitic acid (PA) to oleic acid (OA) and palmitoleic acid (PO), respectively. In this study, through a series of experiments, we showed that Scd-1 and its resulting compound, OA, have a substantial impact on the transformation of CD8+ naïve T cells into effector T cells. Inactivation of Scd-1 triggers the specialization of CD8+ T cells into the Teff subset, enhancing the effector function and mitochondrial metabolism of Teff cells, and OA can partially counteract this. A deeper understanding of lipid metabolism in immune cells and its impact on cell function can lead to new therapeutic approaches for controlling the immune response and improving prognosis.
    Keywords:  differentiation; effector T cells; infection; monounsaturated fatty acid; stearoyl-CoA desaturase
    DOI:  https://doi.org/10.3389/fcimb.2024.1325390
  9. Cell. 2024 Feb 14. pii: S0092-8674(24)00102-8. [Epub ahead of print]
    A versatile CRISPR-Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells.
    Victor Tieu, Elena Sotillo, Jeremy R Bjelajac, Crystal Chen, Meena Malipatlolla, Justin A Guerrero, Peng Xu, Patrick J Quinn, Chris Fisher, Dorota Klysz, Crystal L Mackall, Lei S Qi.
      CRISPR technologies have begun to revolutionize T cell therapies; however, conventional CRISPR-Cas9 genome-editing tools are limited in their safety, efficacy, and scope. To address these challenges, we developed multiplexed effector guide arrays (MEGA), a platform for programmable and scalable regulation of the T cell transcriptome using the RNA-guided, RNA-targeting activity of CRISPR-Cas13d. MEGA enables quantitative, reversible, and massively multiplexed gene knockdown in primary human T cells without targeting or cutting genomic DNA. Applying MEGA to a model of CAR T cell exhaustion, we robustly suppressed inhibitory receptor upregulation and uncovered paired regulators of T cell function through combinatorial CRISPR screening. We additionally implemented druggable regulation of MEGA to control CAR activation in a receptor-independent manner. Lastly, MEGA enabled multiplexed disruption of immunoregulatory metabolic pathways to enhance CAR T cell fitness and anti-tumor activity in vitro and in vivo. MEGA offers a versatile synthetic toolkit for applications in cancer immunotherapy and beyond.
    Keywords:  CAR T cells; CRISPR; Cas13; RNA targeting; T cell exhaustion; cancer immunotherapy; cell therapy; gene editing; metabolic engineering; synthetic biology
    DOI:  https://doi.org/10.1016/j.cell.2024.01.035
  10. Nat Metab. 2024 Feb 22.
    Metabolic engineering for optimized CAR-T cell therapy.
    Sarah J McPhedran, Gillian A Carleton, Julian J Lum.
      The broad effectiveness of T cell-based therapy for treating solid tumour cancers remains limited. This is partly due to the growing appreciation that immune cells must inhabit and traverse a metabolically demanding tumour environment. Accordingly, recent efforts have centred on using genome-editing technologies to augment T cell-mediated cytotoxicity by manipulating specific metabolic genes. However, solid tumours exhibit numerous characteristics restricting immune cell-mediated cytotoxicity, implying a need for metabolic engineering at the pathway level rather than single gene targets. This emerging concept has yet to be put into clinical practice as many questions concerning the complex interplay between metabolic networks and T cell function remain unsolved. This Perspective will highlight key foundational studies that examine the relevant metabolic pathways required for effective T cell cytotoxicity and persistence in the human tumour microenvironment, feasible strategies for metabolic engineering to increase the efficiency of chimeric antigen receptor T cell-based approaches, and the challenges lying ahead for clinical implementation.
    DOI:  https://doi.org/10.1038/s42255-024-00976-2
  11. Curr Opin Biotechnol. 2024 Feb 19. pii: S0958-1669(24)00011-9. [Epub ahead of print]86 103075
    Bridging the gender gap in autoimmunity with T-cell-targeted biomaterials.
    Aida López Ruiz, Eric D Slaughter, April M Kloxin, Catherine A Fromen.
      Autoimmune diseases are caused by malfunctions of the immune system and generally impact women at twice the frequency of men. Many of the most serious autoimmune diseases are accompanied by a dysregulation of T-cell phenotype, both regarding the ratio of CD4+ to CD8+ T-cells and proinflammatory versus regulatory phenotypes. Biomaterials, in the form of particles and hydrogels, have shown promise in ameliorating this dysregulation both in vivo and ex vivo. In this review, we explore the role of T-cells in autoimmune diseases, particularly those with high incidence rates in women, and evaluate the promise and efficacy of innovative biomaterial-based approaches for targeting T-cells.
    DOI:  https://doi.org/10.1016/j.copbio.2024.103075
  12. JCI Insight. 2024 Feb 22. pii: e177141. [Epub ahead of print]
    Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment.
    Ryusuke Hatae, Keith Kyewalabye, Akane Yamamichi, Tiffany Chen, Su Phyu, Pavlina Chuntova, Takahide Nejo, Lauren S Levine, Matthew H Spitzer, Hideho Okada.
      The efficacy of chimeric antigen receptor (CAR)-T therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28-EGFRvIII glioma revealed impaired mitochondrial ATP production and a markedly hypoxic status compared to ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of AMPK activator Metformin and the mTOR inhibitor Rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-gamma coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective anti-glioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28-EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group with fewer Ly6c+ CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.
    Keywords:  Brain cancer; Cancer immunotherapy; Hypoxia; Immunology; Otology
    DOI:  https://doi.org/10.1172/jci.insight.177141
  13. Cell Biochem Funct. 2024 Mar;42(2): e3934
    Discovering the strength of immunometabolism in cancer therapy: Employing metabolic pathways to enhance immune responses.
    Huldani Huldani, Jitendra Malviya, Paul Rodrigues, Ahmed Hjazi, Maha Medha Deorari, Hussein Riyadh Abdul Kareem Al-Hetty, Qutaiba A Qasim, Mohammed Qasim Alasheqi, Ali Ihsan.
      Immunometabolism, which studies cellular metabolism and immune cell function, is a possible cancer treatment. Metabolic pathways regulate immune cell activation, differentiation, and effector functions, crucial to tumor identification and elimination. Immune evasion and tumor growth can result from tumor microenvironment metabolic dysregulation. These metabolic pathways can boost antitumor immunity. This overview discusses immune cell metabolism, including glycolysis, oxidative phosphorylation, amino acid, and lipid metabolism. Amino acid and lipid metabolic manipulations may improve immune cell activity and antitumor immunity. Combination therapy using immunometabolism-based strategies may enhance therapeutic efficacy. The complexity of the metabolic network, biomarker development, challenges, and future approaches are all covered, along with a summary of case studies demonstrating the effectiveness of immunometabolism-based therapy. Metabolomics, stable isotope tracing, single-cell analysis, and computational modeling are also reviewed for immunometabolism research. Personalized and combination treatments are considered. This review adds to immunometabolism expertise and sheds light on metabolic treatments' ability to boost cancer treatment immunological response. Also, in this review, we discussed the immune response in cancer treatment and altering metabolic pathways to increase the immune response against malignancies.
    Keywords:  cancer; immune response; immunometabolism; metabolic pathways
    DOI:  https://doi.org/10.1002/cbf.3934
  14. Biomedicines. 2024 Feb 10. pii: 414. [Epub ahead of print]12(2):
    Mitochondria-Targeted Catalase Does Not Suppress Development of Cellular Senescence during Aging.
    Bronwyn A Mogck, Samantha T Jezak, Christopher D Wiley.
      Cellular senescence is a complex stress response marked by stable proliferative arrest and the secretion of biologically active molecules collectively known as the senescence-associated secretory phenotype (SASP). Mitochondria-derived reactive oxygen species (ROS) have been implicated in aging and age-related processes, including senescence. Stressors that increase ROS levels promote both senescence and the SASP, while reducing mitochondrial ROS or mitochondria themselves can prevent senescence or the SASP. Mitochondrially targeted catalase (mCAT), a transgene that reduces mitochondrial levels of ROS, has been shown to extend the lifespan of murine models and protect against the age-related loss of mitochondrial function. However, it remains unclear whether mCAT can prevent senescence or the SASP. In this study, we investigated the impact of mCAT on senescence in cultured cells and aged mice in order to discover if the lifespan-extending activity of mCAT might be due to the reduction in senescent cells or the SASP. Contrary to expectations, we observed that mCAT does not reduce markers of senescence or the SASP in cultured cells. Moreover, mCAT does not prevent the accumulation of senescent cells or the development of the SASP in adipose tissue from aged mice. These results suggest that mitochondrial ROS may not always play a causal role in the development of senescence during natural aging and underscore the need for a nuanced understanding of the intricate relationship between mitochondrial ROS and cellular senescence.
    Keywords:  SASP; aging; catalase; cellular senescence; mCAT; reactive oxygen specific
    DOI:  https://doi.org/10.3390/biomedicines12020414
  15. Geroscience. 2024 Feb 21.
    Intermittent fasting promotes rejuvenation of immunosenescent phenotypes in aged adipose tissue.
    Kafi N Ealey, Jacques Togo, Ju Hee Lee, Yash Patel, Jae-Ryong Kim, So-Young Park, Hoon-Ki Sung.
      The aging of white adipose tissue (WAT) involves senescence of adipose stem and progenitor cells (ASPCs) and dysregulation of immune cell populations, serving as a major driver of age-associated adipose dysfunction and metabolic diseases. Conversely, the elimination of senescent ASPCs is associated with improvements in overall health. Intermittent fasting (IF), a dietary intervention that incorporates periodic cycles of fasting and refeeding, has been reported to promote weight loss and fat mass reduction and improve glucose and insulin homeostasis in both murine and human studies. While previous studies have assessed the effects of IF on obesity-associated metabolic dysfunction, few studies have examined the aging-specific changes to ASPCs and immune cell populations in WAT. Here, we show that IF in 18-20-month-old mice reduced senescent phenotypes of ASPCs and restored their adipogenic potential. Intriguingly, IF-treated mice exhibited an increase in adipose eosinophils, which has been reported to be associated with improved WAT homeostasis and immunological fitness in aged mice. The observed cellular and metabolic changes suggest that IF may be a feasible lifestyle regimen to reduce cellular senescence which could result in attenuation of downstream aging-induced WAT dysfunction and metabolic diseases.
    Keywords:  Adipose stem and progenitor cells; Eosinophils; Immunosenescence; Intermittent fasting; Rejuvenation; Visceral adipose
    DOI:  https://doi.org/10.1007/s11357-024-01093-4
  16. Nature. 2024 Feb 21.
    IL-10 constrains sphingolipid metabolism to limit inflammation.
    Autumn G York, Mathias H Skadow, Joonseok Oh, Rihao Qu, Quan D Zhou, Wei-Yuan Hsieh, Walter K Mowel, J Richard Brewer, Eleanna Kaffe, Kevin J Williams, Yuval Kluger, Stephen T Smale, Jason M Crawford, Steven J Bensinger, Richard A Flavell.
      Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice-however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2-5. Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that 'metabolic correction' of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.
    DOI:  https://doi.org/10.1038/s41586-024-07098-5
  17. J Transl Med. 2024 Feb 20. 22(1): 183
    An angel or a devil? Current view on the role of CD8+ T cells in the pathogenesis of myasthenia gravis.
    Yong Peng, Huan Yang, Quan Chen, Hong Jin, Ya-Hui Xue, Miao-Qiao Du, Shu Liu, Shun-Yu Yao.
       BACKGROUND: Myasthenia gravis (MG) and the experimental autoimmune MG (EAMG) animal model are characterized by T-cell-induced and B-cell-dominated autoimmune diseases that affect the neuromuscular junction. Several subtypes of CD4+ T cells, including T helper (Th) 17 cells, follicular Th cells, and regulatory T cells (Tregs), contribute to the pathogenesis of MG. However, increasing evidence suggests that CD8+ T cells also play a critical role in the pathogenesis and treatment of MG.
    MAIN BODY: Herein, we review the literature on CD8+ T cells in MG, focusing on their potential effector and regulatory roles, as well as on relevant evidence (peripheral, in situ, cerebrospinal fluid, and under different treatments), T-cell receptor usage, cytokine and chemokine expression, cell marker expression, and Treg, Tc17, CD3+CD8+CD20+ T, and CXCR5+ CD8+ T cells.
    CONCLUSIONS: Further studies on CD8+ T cells in MG are necessary to determine, among others, the real pattern of the Vβ gene usage of autoantigen-specific CD8+ cells in patients with MG, real images of the physiology and function of autoantigen-specific CD8+ cells from MG/EAMG, and the subset of autoantigen-specific CD8+ cells (Tc1, Tc17, and IL-17+IFN-γ+CD8+ T cells). There are many reports of CD20-expressing T (or CD20 + T) and CXCR5+ CD8 T cells on autoimmune diseases, especially on multiple sclerosis and rheumatoid arthritis. Unfortunately, up to now, there has been no report on these T cells on MG, which might be a good direction for future studies.
    Keywords:  CD8+ T cells; Effector T cells; Experimental autoimmune myasthenia gravis; Myasthenia gravis; Regulatory T cells
    DOI:  https://doi.org/10.1186/s12967-024-04965-7
  18. Nature. 2024 Feb 21.
    Author Correction: Senolytic CAR T cells reverse senescence-associated pathologies.
    Corina Amor, Judith Feucht, Josef Leibold, Yu-Jui Ho, Changyu Zhu, Direna Alonso-Curbelo, Jorge Mansilla-Soto, Jacob A Boyer, Xiang Li, Theodoros Giavridis, Amanda Kulick, Shauna Houlihan, Ellinor Peerschke, Scott L Friedman, Vladimir Ponomarev, Alessandra Piersigilli, Michel Sadelain, Scott W Lowe.
      
    DOI:  https://doi.org/10.1038/s41586-024-07197-3
  19. Front Immunol. 2024 ;15 1308070
    The significance of targeting lysosomes in cancer immunotherapy.
    Yanxin Xu, Bo Shao, Yafeng Zhang.
      Lysosomes are intracellular digestive organelles that participate in various physiological and pathological processes, including the regulation of immune checkpoint molecules, immune cell function in the tumor microenvironment, antigen presentation, metabolism, and autophagy. Abnormalities or dysfunction of lysosomes are associated with the occurrence, development, and drug resistance of tumors. Lysosomes play a crucial role and have potential applications in tumor immunotherapy. Targeting lysosomes or harnessing their properties is an effective strategy for tumor immunotherapy. However, the mechanisms and approaches related to lysosomes in tumor immunotherapy are not fully understood at present, and further basic and clinical research is needed to provide better treatment options for cancer patients. This review focuses on the research progress related to lysosomes and tumor immunotherapy in these.
    Keywords:  immunotherapy; lysosomal autophagy; lysosomes; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1308070
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