bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024‒09‒01
nineteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.
  2. Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid.
  3. Attenuated effector T cells are linked to control of chronic HBV infection.
  4. Current Strategies to Improve Chimeric Antigen Receptor T (CAR-T) Cell Persistence.
  5. A nutrigeroscience approach: Dietary macronutrients and cellular senescence.
  6. Fate induction in CD8 CAR T cells through asymmetric cell division.
  7. Clonal succession after prolonged antiretroviral therapy rejuvenates CD8+ T cell responses against HIV-1.
  8. Immune suppression by human thymus-derived effector Tregs relies on glucose/lactate-fueled fatty acid synthesis.
  9. Hepatitis B vaccine responders show higher frequencies of CD8+ effector memory and central memory T cells compared to non-responders.
  10. Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and T cell proliferation.
  11. T-Cell Senescence in Human Metabolic Diseases.
  12. LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness.
  13. Reprogramming hematopoietic stem cell metabolism in lung cancer: glycolysis, oxidative phosphorylation, and the role of 2-DG.
  14. Age-related increase of CD38 directs osteoclastogenic potential of monocytic myeloid-derived suppressor cells through mitochondrial dysfunction in male mice.
  15. At the heart of cardiac-specific regulatory T cell differentiation.
  16. Cytotoxic T cells drive doxorubicin-induced cardiac fibrosis and systolic dysfunction.
  17. Indirect suppression of CD4 T cell activation through LAG-3-mediated trans-endocytosis of MHC class II.
  18. The hidden strength of CD8+ T cells in chronic hepatitis B.
  19. P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.
  1. Nat Immunol. 2024 Aug 28.
    NaCl enhances CD8+ T cell effector functions in cancer immunotherapy.
    Caterina Scirgolea, Rosa Sottile, Marco De Luca, Alberto Susana, Silvia Carnevale, Simone Puccio, Valentina Ferrari, Veronica Lise, Giorgia Contarini, Alice Scarpa, Eloise Scamardella, Simona Feno, Chiara Camisaschi, Gabriele De Simone, Gianluca Basso, Desiree Giuliano, Emilia Maria Cristina Mazza, Luca Gattinoni, Rahul Roychoudhuri, Emanuele Voulaz, Diletta Di Mitri, Matteo Simonelli, Agnese Losurdo, Davide Pozzi, Carlson Tsui, Axel Kallies, Sara Timo, Giuseppe Martano, Elettra Barberis, Marcello Manfredi, Maria Rescigno, Sebastien Jaillon, Enrico Lugli.
      CD8+ T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+ T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+ T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+ T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+ T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+ T cell effector function, with potential implications for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-024-01923-9
  2. Sci Transl Med. 2024 Aug 28. 16(762): eadk7399
    Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid.
    Ying Liu, Feng Wang, Dongxue Peng, Dan Zhang, Luping Liu, Jun Wei, Jian Yuan, Luyao Zhao, Huimin Jiang, Tingting Zhang, Yunxuan Li, Chenxi Zhao, Shuhua He, Jie Wu, Yechao Yan, Peitao Zhang, Chunyi Guo, Jiaming Zhang, Xia Li, Huan Gao, Ke Li.
      CD8+ T cell activation leads to the rapid proliferation and differentiation of effector T cells (Teffs), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8+ Teffs, the mechanisms that regulate CD8+ T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8+ T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8+ T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8+ T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8+ T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8+ T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti-programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8+ T cells and identify that TME accumulated lactic acid inhibits CD8+ T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8+ T cell-mediated antitumor effects.
    DOI:  https://doi.org/10.1126/scitranslmed.adk7399
  3. Nat Immunol. 2024 Sep;25(9): 1650-1662
    Attenuated effector T cells are linked to control of chronic HBV infection.
    Kathrin Heim, Sagar, Özlem Sogukpinar, Sian Llewellyn-Lacey, David A Price, Florian Emmerich, Anke R M Kraft, Markus Cornberg, Sophie Kielbassa, Percy Knolle, Dirk Wohlleber, Bertram Bengsch, Tobias Boettler, Christoph Neumann-Haefelin, Robert Thimme, Maike Hofmann.
      Hepatitis B virus (HBV)-specific CD8+ T cells play a dominant role during acute-resolving HBV infection but are functionally impaired during chronic HBV infection in humans. These functional deficits have been linked with metabolic and phenotypic heterogeneity, but it has remained unclear to what extent different subsets of HBV-specific CD8+ T cells still suppress viral replication. We addressed this issue by deep profiling, functional testing and perturbation of HBV-specific CD8+ T cells during different phases of chronic HBV infection. Our data revealed a mechanism of effector CD8+ T cell attenuation that emerges alongside classical CD8+ T cell exhaustion. Attenuated HBV-specific CD8+ T cells were characterized by cytotoxic properties and a dampened effector differentiation program, determined by antigen recognition and TGFβ signaling, and were associated with viral control during chronic HBV infection. These observations identify a distinct subset of CD8+ T cells linked with immune efficacy in the context of a chronic human viral infection with immunotherapeutic potential.
    DOI:  https://doi.org/10.1038/s41590-024-01928-4
  4. Cureus. 2024 Jul;16(7): e65291
    Current Strategies to Improve Chimeric Antigen Receptor T (CAR-T) Cell Persistence.
    Soren K Ghorai, Ashley N Pearson.
      Chimeric antigen receptor T (CAR-T) cell therapy has transformed the field of immunology by redirecting T lymphocytes toward tumor antigens. Despite successes in attaining high remission rates as high as 90%, the performance of CAR therapy is limited by the survival of T cells. T cell persistence is crucial as it sustains immune response against malignancies, playing a critical role in cancer treatment outcomes. This review explores various approaches to improve CAR-T cell persistence, focusing on the choice between autologous and allogeneic cell sources, optimization of culture conditions for T cell subsets, metabolite adjustments to modify T cell metabolism, the use of oncolytic viruses (OVs), and advancements in CAR design. Autologous CAR-T cells generally exhibit longer persistence but are less accessible and cost-effective than their allogeneic counterparts. Optimizing culture conditions by promoting TSCM and TCM cell differentiation has also demonstrated increased persistence, as seen with the use of cytokine combinations like IL-7 and IL-15. Metabolic adjustments, such as using 2-deoxy-D-glucose (2-DG) and L-arginine, have enhanced the formation of memory T cells, leading to improved antitumor activity. OVs, when combined with CAR-T therapy, can amplify CAR-T cell penetration and persistence in solid tumors, although further clinical validation is needed. Advances in CAR design from second to fifth generations have progressively improved T cell activation and survival, with fifth-generation CARs demonstrating strong cytokine-mediated signaling and long-lasting persistence. Understanding the underlying mechanisms behind these strategies is essential for maximizing the potential of CAR-T therapy in treating cancer. Further research is needed to improve safety and efficacy and seamlessly integrate the discussed strategies into the manufacturing process.
    Keywords:  adaptive immunity; car-t persistence; car-t therapy; immune evasion; immunotherapy
    DOI:  https://doi.org/10.7759/cureus.65291
  5. Cell Metab. 2024 Aug 15. pii: S1550-4131(24)00327-9. [Epub ahead of print]
    A nutrigeroscience approach: Dietary macronutrients and cellular senescence.
    Mariah F Calubag, Paul D Robbins, Dudley W Lamming.
      Cellular senescence, a process in which a cell exits the cell cycle in response to stressors, is one of the hallmarks of aging. Senescence and the senescence-associated secretory phenotype (SASP)-a heterogeneous set of secreted factors that disrupt tissue homeostasis and promote the accumulation of senescent cells-reprogram metabolism and can lead to metabolic dysfunction. Dietary interventions have long been studied as methods to combat age-associated metabolic dysfunction, promote health, and increase lifespan. A growing body of literature suggests that senescence is responsive to diet, both to calories and specific dietary macronutrients, and that the metabolic benefits of dietary interventions may arise in part through reducing senescence. Here, we review what is currently known about dietary macronutrients' effect on senescence and the SASP, the nutrient-responsive molecular mechanisms that may mediate these effects, and the potential for these findings to inform the development of a nutrigeroscience approach to healthy aging.
    Keywords:  branched-chain amino acids; cellular senescence; healthspan; macronutrients; nutrigeroscience; protein; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.025
  6. Nature. 2024 Aug 28.
    Fate induction in CD8 CAR T cells through asymmetric cell division.
    Casey S Lee, Sisi Chen, Corbett T Berry, Andre R Kelly, Patrick J Herman, Sangwook Oh, Roddy S O'Connor, Aimee S Payne, Christoph T Ellebrecht.
      Early expansion and long-term persistence predict efficacy of chimeric antigen receptor T cells (CARTs)1-7, but mechanisms governing effector versus memory CART differentiation and whether asymmetric cell division induces differential fates in human CARTs remain unclear. Here we show that target-induced proximity labelling enables isolation of first-division proximal-daughter and distal-daughter CD8 CARTs that asymmetrically distribute their surface proteome and transcriptome, resulting in divergent fates. Target-engaged CARs remain on proximal daughters, which inherit a surface proteome resembling activated-undivided CARTs, whereas the endogenous T cell receptor and CD8 enrich on distal daughters, whose surface proteome resembles resting CARTs, correlating with glycolytic and oxidative metabolism, respectively. Despite memory-precursor phenotype and in vivo longevity, distal daughters demonstrate transient potent cytolytic activity similar to proximal daughters, uncovering an effector-like state in distal daughters destined to become memory CARTs. Both partitioning of pre-existing transcripts and changes in RNA velocity contribute to asymmetry of fate-determining factors, resulting in diametrically opposed transcriptional trajectories. Independent of naive, memory or effector surface immunophenotype, proximal-daughter CARTs use core sets of transcription factors known to support proliferation and effector function. Conversely, transcription factors enriched in distal daughters restrain differentiation and promote longevity, evidenced by diminished long-term in vivo persistence and function of distal-daughter CARTs after IKZF1 disruption. These studies establish asymmetric cell division as a framework for understanding mechanisms of CART differentiation and improving therapeutic outcomes.
    DOI:  https://doi.org/10.1038/s41586-024-07862-7
  7. Nat Immunol. 2024 Sep;25(9): 1555-1564
    Clonal succession after prolonged antiretroviral therapy rejuvenates CD8+ T cell responses against HIV-1.
    Eoghann White, Laura Papagno, Assia Samri, Kenji Sugata, Boris Hejblum, Amy R Henry, Daniel C Rogan, Samuel Darko, Patricia Recordon-Pinson, Yasmine Dudoit, Sian Llewellyn-Lacey, Lisa A Chakrabarti, Florence Buseyne, Stephen A Migueles, David A Price, Marie-Aline Andreola, Yorifumi Satou, Rodolphe Thiebaut, Christine Katlama, Brigitte Autran, Daniel C Douek, Victor Appay.
      Human immunodeficiency virus 1 (HIV-1) infection is characterized by a dynamic and persistent state of viral replication that overwhelms the host immune system in the absence of antiretroviral therapy (ART). The impact of prolonged treatment on the antiviral efficacy of HIV-1-specific CD8+ T cells has nonetheless remained unknown. Here, we used single-cell technologies to address this issue in a cohort of aging individuals infected early during the pandemic and subsequently treated with continuous ART. Our data showed that long-term ART was associated with a process of clonal succession, which effectively rejuvenated HIV-1-specific CD8+ T cell populations in the face of immune senescence. Tracking individual transcriptomes further revealed that initially dominant CD8+ T cell clonotypes displayed signatures of exhaustion and terminal differentiation, whereas newly dominant CD8+ T cell clonotypes displayed signatures of early differentiation and stemness associated with natural control of viral replication. These findings reveal a degree of immune resilience that could inform adjunctive treatments for HIV-1.
    DOI:  https://doi.org/10.1038/s41590-024-01931-9
  8. Cell Rep. 2024 Aug 23. pii: S2211-1247(24)01032-5. [Epub ahead of print]43(9): 114681
    Immune suppression by human thymus-derived effector Tregs relies on glucose/lactate-fueled fatty acid synthesis.
    Sander de Kivit, Mark Mensink, Sarantos Kostidis, Rico J E Derks, Esther A Zaal, Marieke Heijink, Lotte J Verleng, Evert de Vries, Ellen Schrama, Niek Blomberg, Celia R Berkers, Martin Giera, Jannie Borst.
      Regulatory T cells (Tregs) suppress pro-inflammatory conventional T cell (Tconv) responses. As lipids impact cell signaling and function, we compare the lipid composition of CD4+ thymus-derived (t)Tregs and Tconvs. Lipidomics reveal constitutive enrichment of neutral lipids in Tconvs and phospholipids in tTregs. TNFR2-co-stimulated effector tTregs and Tconvs are both glycolytic, but only in tTregs are glycolysis and the tricarboxylic acid (TCA) cycle linked to a boost in fatty acid (FA) synthesis (FAS), supported by relevant gene expression. FA chains in tTregs are longer and more unsaturated than in Tconvs. In contrast to Tconvs, tTregs effectively use either lactate or glucose for FAS and rely on this process for proliferation. FASN and SCD1, enzymes responsible for FAS and FA desaturation, prove essential for the ability of tTregs to suppress Tconvs. These data illuminate how effector tTregs can thrive in inflamed or cancerous tissues with limiting glucose but abundant lactate levels.
    Keywords:  (regulatory) T cell; CP: Immunology; CP: Metabolism; costimulation; fatty acids; glycolysis; immune suppression; isotopologue tracing; lactate; lipidomics; mass spectrometry; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.114681
  9. Scand J Immunol. 2024 Aug 27. e13402
    Hepatitis B vaccine responders show higher frequencies of CD8+ effector memory and central memory T cells compared to non-responders.
    Mahsa Eshkevar Vakili, Niloofar Mashhadi, Mohammad Reza Ataollahi, Seppo Meri, Dieter Kabelitz, Kurosh Kalantar.
      Hepatitis B (HB) infection is a major global health problem. There is limited knowledge about HB vaccination-induced immune memory responses. We compared the frequency of CD8+ memory T cell subsets between responders (RSs) and non-responders (NRs) to HB vaccination. Blood samples were collected from RSs and NRs. PBMCs were cultured in the presence of Hepatitis B surface antigens (HBsAg) and PHA for 48 h to restimulate CD8+ memory T cells and T cell memory subsets were detected by flow cytometry using memory cell markers. The frequency of TEM, TCM, and TCM hi was significantly higher in responders compared to non-responders (p = 0.024, 0.022, and 0.047, respectively). Additionally, we report a positive correlation between the frequency of TEM cells in RSs with age and anti-HBsAb level (p = 0.03 and rs = 0.5; p = 0.01 and rs = 0.06). Responders display a higher level of CD8+ T cell-mediated immunity. Therefore, we suggest a possible defect in the formation of immunological CD8+ memory T cells in NRs and it may reduce antibody production compared to the RSs, although more experiments are needed.
    Keywords:  CD8+ memory T cells; T central memory; T effector memory; T stem cell memory; hepatitis B vaccine
    DOI:  https://doi.org/10.1111/sji.13402
  10. Nat Commun. 2024 Aug 27. 15(1): 7372
    Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and T cell proliferation.
    Jian-Xin Lin, Meili Ge, Cheng-Yu Liu, Ronald Holewinski, Thorkell Andresson, Zu-Xi Yu, Tesfay Gebregiorgis, Rosanne Spolski, Peng Li, Warren J Leonard.
      Cytokine-mediated STAT5 protein activation is vital for lymphocyte development and function. In vitro tyrosine phosphorylation of a C-terminal tyrosine is critical for activation of STAT5A and STAT5B; however, the importance of STAT5 tyrosine phosphorylation in vivo has not been assessed. Here we generate Stat5a and Stat5b tyrosine-to-phenylalanine mutant knockin mice and find they have greatly reduced CD8+ T-cell numbers and profoundly diminished IL-2-induced proliferation of these cells, and this correlates with reduced induction of Myc, pRB, a range of cyclins and CDKs, and a partial G1→S phase-transition block. These mutant CD8+ T cells also exhibit decreased IL-2-mediated activation of pERK and pAKT, which we attribute in part to diminished expression of IL-2Rβ and IL-2Rγ. Our findings thus demonstrate that tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling. Moreover, our transcriptomic and proteomic analyses elucidate the molecular basis of the IL-2-induced proliferation of CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41467-024-50925-6
  11. Diabetes Metab J. 2024 Aug 28.
    T-Cell Senescence in Human Metabolic Diseases.
    Ha Thi Nga, Thi Linh Nguyen, Hyon-Seung Yi.
      Immunosenescence denotes a state of dysregulated immune cell function characterized by a confluence of factors, including arrested cell cycle, telomere shortening, markers of cellular stress, mitochondrial dysfunction, loss of proteostasis, epigenetic reprogramming, and secretion of proinflammatory mediators. This state primarily manifests during the aging process but can also be induced in various pathological conditions, encompassing chronic viral infections, autoimmune diseases, and metabolic disorders. Age-associated immune system alterations extend to innate and adaptive immune cells, with T-cells exhibiting heightened susceptibility to immunosenescence. In particular, senescent T-cells have been identified in the context of metabolic disorders such as obesity, diabetes, and cardiovascular diseases. Recent investigations suggest a direct link between T-cell senescence, inflammation, and insulin resistance. The perturbation of biological homeostasis by senescent T-cells appears intricately linked to the initiation and progression of metabolic diseases, particularly through inflammation-mediated insulin resistance. Consequently, senescent T-cells are emerging as a noteworthy therapeutic target. This review aims to elucidate the intricate relationship between metabolic diseases and T-cell senescence, providing insights into the potential roles of senescent T-cells in the pathogenesis of metabolic disorders. Through a comprehensive examination of current research findings, this review seeks to contribute to a deeper understanding of the complex interplay between immunosenescence and metabolic health.
    Keywords:  Aging; Diabetes mellitus; Metabolic diseases; T-cell senescence
    DOI:  https://doi.org/10.4093/dmj.2024.0140
  12. Nat Commun. 2024 Aug 27. 15(1): 7366
    LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness.
    Isabella Pallavicini, Teresa Maria Frasconi, Carlotta Catozzi, Elena Ceccacci, Silvia Tiberti, Dorothee Haas, Jule Samson, Christoph Heuser-Loy, Carina B Nava Lauson, Marta Mangione, Elisa Preto, Alberto Bigogno, Eleonora Sala, Matteo Iannacone, Ciro Mercurio, Luca Gattinoni, Ignazio Caruana, Mirela Kuka, Luigi Nezi, Saverio Minucci, Teresa Manzo.
      The lysine-specific histone demethylase 1 A (LSD1) is involved in antitumor immunity; however, its role in shaping CD8 + T cell (CTL) differentiation and function remains largely unexplored. Here, we show that pharmacological inhibition of LSD1 (LSD1i) in CTL in the context of adoptive T cell therapy (ACT) elicits phenotypic and functional alterations, resulting in a robust antitumor immunity in preclinical models in female mice. In addition, the combination of anti-PDL1 treatment with LSD1i-based ACT eradicates the tumor and leads to long-lasting tumor-free survival in a melanoma model, complementing the limited efficacy of the immune or epigenetic therapy alone. Collectively, these results demonstrate that LSD1 modulation improves antitumoral responses generated by ACT and anti-PDL1 therapy, providing the foundation for their clinical evaluation.
    DOI:  https://doi.org/10.1038/s41467-024-51500-9
  13. Biol Direct. 2024 Aug 24. 19(1): 73
    Reprogramming hematopoietic stem cell metabolism in lung cancer: glycolysis, oxidative phosphorylation, and the role of 2-DG.
    Ziqi Guo, Yaping Liu, Xin Li, Yuying Huang, Zuping Zhou, Cheng Yang.
      Hematopoietic stem cells (HSCs) exhibit significant functional and metabolic alterations within the lung cancer microenvironment, contributing to tumor progression and immune evasion by increasing differentiation into myeloid-derived suppressor cells (MDSCs). Our aim is to analyze the metabolic transition of HSCs from glycolysis to oxidative phosphorylation (OXPHOS) in lung cancer and determine its effects on HSC functionality. Using a murine Lewis Lung Carcinoma lung cancer model, we conducted metabolic profiling of long-term and short-term HSCs, as well as multipotent progenitors, comparing their metabolic states in normal and cancer conditions. We measured glucose uptake using 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino]-2-Deoxyglucose (2-NBDG) and assessed levels of lactate, acetyl-coenzyme A, and ATP. Mitochondrial functionality was evaluated through flow cytometry, alongside the impact of the glucose metabolism inhibitor 2-DG on HSC differentiation and mitochondrial activity. HSCs under lung cancer conditions showed increased glucose uptake and lactate production, with an associated rise in OXPHOS activity, marking a metabolic shift. Treatment with 2-DG led to decreased T-HSCs and MDSCs and an increased red blood cell count, highlighting its potential to influence metabolic and differentiation pathways in HSCs. This study provides novel insights into the metabolic reprogramming of HSCs in lung cancer, emphasizing the critical shift from glycolysis to OXPHOS and its implications for the therapeutic targeting of cancer-related metabolic pathways.
    Keywords:  2-DG; Glycolysis; Hematopoietic stem cells; Lung cancer; Metabolic reprogramming; Oxidative phosphorylation; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13062-024-00514-w
  14. Aging Cell. 2024 Aug 23. e14298
    Age-related increase of CD38 directs osteoclastogenic potential of monocytic myeloid-derived suppressor cells through mitochondrial dysfunction in male mice.
    Ramkumar Thiyagarajan, Lixia Zhang, Omar D Glover, Kyu Hwan Kwack, Sara Ahmed, Emma Murray, Nanda Kumar Yellapu, Jonathan Bard, Kenneth L Seldeen, Spencer R Rosario, Bruce R Troen, Keith L Kirkwood.
      An aged immune system undergoes substantial changes where myelopoiesis dominates within the bone marrow. Monocytic-MDSCs (M-MDSCs) have been found to play an important role in osteoclastogenesis and bone resorption. In this study, we sought to provide a more comprehensive understanding of the osteoclastogenic potential of bone marrow M-MDSCs during normal aging through transcriptomic and metabolic changes. Using young mature and aged mice, detailed immunophenotypic analyses of myeloid cells revealed that the M-MDSCs were not increased in bone marrow, however M-MDSCS were significantly expanded in peripheral tissues. Although aged mice exhibited a similar number of M-MDSCs in bone marrow, these M-MDSCs had significantly higher osteoclastogenic potential and greater demineralization activity. Intriguingly, osteoclast progenitors from aged bone marrow M-MDSCs exhibited greater mitochondrial respiration rate and glucose metabolism. Further, transcriptomic analyses revealed the upregulation of mitochondrial oxidative phosphorylation and glucose metabolism genes. Interestingly, there was 8-fold increase in Cd38 mRNA gene expression, consistent with the Mouse Aging Cell Atlas transcriptomic database, and confirmed by qRT-PCR. CD38 regulates NAD+ availability, and 78c, a small molecule inhibitor of CD38, reduced the mitochondrial oxygen consumption rate and glucose metabolism and inhibited the osteoclastogenic potential of aged mice bone marrow-derived M-MDSCs. These results indicate that the age-related increase in Cd38 expression in M-MDSCs bias the transcriptome of M-MDSCs towards osteoclastogenesis. This enhanced understanding of the mechanistic underpinnings of M-MDSCs and their osteoclastogenesis during aging could lead to new therapeutic approaches for age-related bone loss and promote healthy aging.
    Keywords:  aging; bone resorption; metabolism; myeloid‐derived suppressor cells; osteoclasts
    DOI:  https://doi.org/10.1111/acel.14298
  15. Nat Cardiovasc Res. 2023 Mar;2(3): 224
    At the heart of cardiac-specific regulatory T cell differentiation.
    Elisa Martini.
      
    DOI:  https://doi.org/10.1038/s44161-023-00258-2
  16. Nat Cardiovasc Res. 2024 Aug;3(8): 970-986
    Cytotoxic T cells drive doxorubicin-induced cardiac fibrosis and systolic dysfunction.
    Abraham L Bayer, Maria A Zambrano, Sasha Smolgovsky, Zachary L Robbe, Abul Ariza, Kuljeet Kaur, Machlan Sawden, Anne Avery, Cheryl London, Aarti Asnani, Pilar Alcaide.
      Doxorubicin, the most prescribed chemotherapeutic drug, causes dose-dependent cardiotoxicity and heart failure. However, our understanding of the immune response elicited by doxorubicin is limited. Here we show that an aberrant CD8+ T cell immune response following doxorubicin-induced cardiac injury drives adverse remodeling and cardiomyopathy. Doxorubicin treatment in non-tumor-bearing mice increased circulating and cardiac IFNγ+CD8+ T cells and activated effector CD8+ T cells in lymphoid tissues. Moreover, doxorubicin promoted cardiac CD8+ T cell infiltration and depletion of CD8+ T cells in doxorubicin-treated mice decreased cardiac fibrosis and improved systolic function. Doxorubicin treatment induced ICAM-1 expression by cardiac fibroblasts resulting in enhanced CD8+ T cell adhesion and transformation, contact-dependent CD8+ degranulation and release of granzyme B. Canine lymphoma patients and human patients with hematopoietic malignancies showed increased circulating CD8+ T cells after doxorubicin treatment. In human cancer patients, T cells expressed IFNγ and CXCR3, and plasma levels of the CXCR3 ligands CXCL9 and CXCL10 correlated with decreased systolic function.
    DOI:  https://doi.org/10.1038/s44161-024-00507-y
  17. Cell Rep. 2024 Aug 21. pii: S2211-1247(24)01006-4. [Epub ahead of print] 114655
    Indirect suppression of CD4 T cell activation through LAG-3-mediated trans-endocytosis of MHC class II.
    Ei Wakamatsu, Hiroaki Machiyama, Hiroko Toyota, Arata Takeuchi, Ryuji Hashimoto, Haruo Kozono, Tadashi Yokosuka.
      Blockade of immune checkpoint receptors has shown outstanding efficacy for tumor immunotherapy. Promising treatment with anti-lymphocyte-activation gene-3 (LAG-3) has already been recognized as the next efficacious treatment, but there is still limited understanding of the mechanism of LAG-3-mediated immune suppression. Here, utilizing high-resolution molecular imaging, we find a mechanism of CD4 T cell suppression via LAG-3, in which LAG-3-bound major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) gather at the central region of an immunological synapse and are trans-endocytosed by T cell receptor-driven internalization motility toward CD4 and CD8 T cells expressing LAG-3. Downregulation of MHC class II molecules on APCs thus results in the attenuation of their antigen-presentation function and impairment of CD4 T cell activation. From these data, anti-LAG-3 treatment is suggested to have potency to directly block the inhibitory signaling via LAG-3 and simultaneously reduce MHC class II expression on APCs by LAG-3-mediated trans-endocytosis for recovery from T cell exhaustion.
    Keywords:  CP: Immunology; LAG-3; MHC class II; T cell; T cell receptor internalization; indirect suppression; trans-endocytosis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114655
  18. Nat Immunol. 2024 Sep;25(9): 1515-1516
    The hidden strength of CD8+ T cells in chronic hepatitis B.
    Francesco Andreata, Matteo Iannacone.
      
    DOI:  https://doi.org/10.1038/s41590-024-01939-1
  19. Nat Commun. 2024 Aug 28. 15(1): 7458
    P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.
    Xiangli Jiang, Ali Hyder Baig, Giuliana Palazzo, Rossella Del Pizzo, Toman Bortecen, Sven Groessl, Esther A Zaal, Cinthia Claudia Amaya Ramirez, Alexander Kowar, Daniela Aviles-Huerta, Celia R Berkers, Wilhelm Palm, Darjus Tschaharganeh, Jeroen Krijgsveld, Fabricio Loayza-Puch.
      Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance.
    DOI:  https://doi.org/10.1038/s41467-024-51901-w
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