bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–03–16
fifteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Metabolic Signaling as a Driver of T Cell Aging.
  2. General and individualized changes in T cell immunity during aging.
  3. Fish requires FasL to facilitate CD8+ T-cell function and antimicrobial immunity.
  4. T Cell Development: From T-Lineage Specification to Intrathymic Maturation.
  5. A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.
  6. The crosstalk between broad epigenetic modification and T cell metabolism within tumor microenvironment.
  7. The NAE1-mediated neddylation operates as an essential post-translational modification checkpoint for effector CD8+ T cells.
  8. IL-15 complex enhances agonistic anti-CD40 + anti-PDL1 by correcting the T-bet to Tox ratio in CD8+ T cells infiltrating pancreatic ductal adenocarcinoma.
  9. CD31 + naïve T cells associate with immunosenescence and responsiveness to multiple vaccines in older adults.
  10. Age and Latent Cytomegalovirus Infection Do Not Affect the Magnitude of De Novo SARS-CoV-2-Specific CD8+ T Cell Responses.
  11. MyD88 determines T cell fate through BCAP-PI3K signaling.
  12. Transient inhibition of type I interferon enhances CD8+ T cell stemness and vaccine protection.
  13. Distinctive CD8+ T cell activation by antigen-presenting plasmacytoid dendritic cells compared to conventional dendritic cells.
  14. Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies.
  15. Sphingolipid metabolism drives mitochondria remodeling during aging and oxidative stress.
  1. Immune Netw. 2025 Feb;25(1): e14
    Metabolic Signaling as a Driver of T Cell Aging.
    Minju Choi, Sujin Choi, Minkyeong Cho, Chulwoo Kim.
      Aging significantly diminishes T cell immunity, increasing susceptibility to infections and reducing vaccine efficacy in older individuals. Metabolism plays a key role in T cell function, shaping their energy requirements, activation, and differentiation. Recent studies highlight altered metabolic signaling as a pivotal factor in T cell aging, influencing the ability of T cells to maintain quiescence, respond to activation, and differentiate into functional subsets. Aberrant metabolic pathways disrupt the quiescence of aged T cells and skew their differentiation toward short-lived, pro-inflammatory effector T cells while hindering the generation of long-lived memory and T follicular helper cells. These changes contribute to a hyper-inflammatory state, exacerbate chronic low-grade inflammation, and compromise immune homeostasis. In this review, we explore how metabolic signaling is altered during T cell aging and the resulting functional impacts. We also discuss therapeutic approaches aimed at restoring proper T cell differentiation, improving vaccine responses, and rejuvenating immune function in older populations.
    Keywords:  Inflammaging; Memory T cells; Metabolic signaling; T cell aging; T cell differentiation; Vaccine
    DOI:  https://doi.org/10.4110/in.2025.25.e14
  2. J Immunol. 2025 Feb 15. pii: vkae033. [Epub ahead of print]
    General and individualized changes in T cell immunity during aging.
    Nianbin Song, Mostafa A Elbahnasawy, Nan-Ping Weng.
      Functional alterations with age are observed in all human systems, but the aging of the adaptive immune system displays both general changes affecting all individuals, and idiosyncratic changes that are unique to individuals. In the T cell compartment, general aging manifests in three ways: (1) the reduction of naïve T cells, (2) the accumulation of differentiated memory T cells, and (3) a reduced overall T cell receptor (TCR) repertoire. Idiosyncratic impacts of aging, such as changes in the TCR repertoires of altered memory and naïve T cells are shaped by each person's life exposures. Recent advancements in single-cell sequencing provide new information including the identification of new subpopulations of T cells, characteristics of transcriptome changes in T cells and their TCR clonotype with age, and measurement of individual cell age. Here, we focus on the changes in T cell subpopulations, transcriptomes and TCR repertoires in overall and antigen-specific T cell population with aging.
    Keywords:  CD4+ T cells; CD8+ T cells; TCR repertoire; aging; species richness
    DOI:  https://doi.org/10.1093/jimmun/vkae033
  3. J Immunol. 2025 Mar 10. pii: vkaf022. [Epub ahead of print]
    Fish requires FasL to facilitate CD8+ T-cell function and antimicrobial immunity.
    Kang Li, Yating Zhu, Zhichao Fang, Ming Geng, Jiansong Zhang, Yuying Zheng, Yi Cao, Xiumei Wei, Jialong Yang.
      Although bony fish have CD8+ T cells, the mechanisms by which these early-evolved cytotoxic cells combat intracellular pathogens remain unclear. In the present study, using Nile tilapia as a model, we investigated the detailed function, mechanism, and evolutionary pattern concerning CD8+ T cells. By depleting CD8+ T cells, they are found essential in combating Edwardsiella piscicida infection. Using siRNA interference, we propose that unlike the strategy predominantly relying on perforin/granzyme in mammals, CD8+ T-cell effector function is mediated by both FasL and perforin/granzyme in fish. Upon E. piscicida infection, FasL is induced to express in CD8+ T cells; both recombinant FasL and adoptively transferred FasL+CD8+ T cells facilitate the apoptosis of target cells. Meanwhile, tilapia FasL also triggers the apoptosis of T cells to archive homeostasis. Since advances in mammals highlight the indispensable role of FasL in maintaining CD8+ T-cell homeostasis, rather than in effector function or anti-infective immunity, we therefore propose the unique dual function of FasL in executing effector function and maintaining homeostasis in fish. Mechanistically, tilapia T cells utilize mTORC1/c-Myc axis to regulate pathogen-induced FasL expression, which binds to Fas and activates caspase-8/caspase-3 pathway, mediating apoptosis in target cells and T cells themselves. This represents a novel mechanism underpinning CD8+ T-cell function in fish. Our findings demonstrate that CD8+ T cells reshaped the FasL-dependent strategy throughout evolution, thereby enhancing the precision and specificity of adaptive immunity.
    Keywords:  CD8+ T cells; FasL; adaptive immunity; evolution; tilapia
    DOI:  https://doi.org/10.1093/jimmun/vkaf022
  4. Adv Exp Med Biol. 2025 ;1471 81-137
    T Cell Development: From T-Lineage Specification to Intrathymic Maturation.
    Mahdieh Golzari-Sorkheh, Kogulan Yoganathan, Edward L Y Chen, Jastaranpreet Singh, Juan Carlos Zúñiga-Pflücker.
      T cell development occurs in the thymus in both mice and humans. Upon entry into the thymus, bone marrow-derived blood-borne progenitors receive instructive signals, including Notch signaling, to eliminate their potential to develop into alternative immune lineages while committing to the T cell fate. Upon T-lineage commitment, developing T cells receive further instructional cues to generate different T cell sublineages, which together possess diverse immunological functions to provide host immunity. Over the years, numerous studies have contributed to a greater understanding of key thymic signals that govern T cell differentiation and subset generation. Here, we review these critical signaling factors that govern the different stages of both mouse and human T cell development, while also focusing on the transcriptional changes that mediate T cell identity and diversity.
    DOI:  https://doi.org/10.1007/978-3-031-77921-3_4
  5. Nat Metab. 2025 Mar 10.
    A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.
    Samantha Pretto, Qian Yu, Pierre Bourdely, Sarah Trusso Cafarello, Heleen H Van Acker, Joren Verelst, Elena Richiardone, Lotte Vanheer, Amir Roshanzadeh, Franziska Schneppenheim, Charlotte Cresens, Maria Livia Sassano, Jonas Dehairs, Martin Carion, Shehab Ismail, Patrizia Agostinis, Susana Rocha, Tobias Bald, Johan Swinnen, Cyril Corbet, Sophia Y Lunt, Bernard Thienpont, Mario Di Matteo, Massimiliano Mazzone.
      Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses.
    DOI:  https://doi.org/10.1038/s42255-025-01233-w
  6. Int Immunopharmacol. 2025 Mar 10. pii: S1567-5769(25)00400-X. [Epub ahead of print]152 114410
    The crosstalk between broad epigenetic modification and T cell metabolism within tumor microenvironment.
    Han Gong, Dan Nie, Zhengyu Li.
      T cells play an important role in adaptive immune responses, providing antigen specificity for pathogen and tumor recognition. Recent studies have elucidated the complex interplay between T cell metabolism and broad epigenetic modifications in response to tumors, occurring at transcriptional, post-transcriptional, and post-translational levels. At the transcriptional level, gene expression is regulated through mechanisms such as DNA methylation, chromatin remodeling, and transcription factor activity. Post-transcriptionally, gene expression is further modulated by non-coding RNAs and RNA modifications, an area of increasing research interest. In addition, histone proteins are primarily regulated by well-established post-translational modifications (PTMs), including acetylation and methylation. Novel PTMs such as succinylation, glycosylation, glutamylation, and lactylation add complexity to the regulation and warrant further investigation. At present, the interaction between CD8+ T cell metabolism and epigenetic modifications in response to malignancies has been reported extensively. However, the interplay in CD4+ T cells remains less understood. In this review, we introduce the differentiation trajectories of T cells and critically evaluate existing interplay between metabolic activity and epigenetic modifications influences the functional dynamics in both CD8+ and CD4+ T cells, offering promising avenues for the development of novel cancer immunotherapies.
    Keywords:  Cancer; Metabolism; Post-transcriptional modification; Post-translational modifications; T cells; Transcriptional modification
    DOI:  https://doi.org/10.1016/j.intimp.2025.114410
  7. Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2424061122
    The NAE1-mediated neddylation operates as an essential post-translational modification checkpoint for effector CD8+ T cells.
    Jiacheng Jin, Ruohan Zhang, Jianying Li, Fengxia Gao, Zhiwei Liao, Yanbao Yu, Yi Wang, Donna Bucci, Min Xiao, Ruilin Ma, Qin Ma, Shuaixin Gao, Jerry Lio, Fernanda Novais, Stanley Ching-Cheng Huang, Jiangjiang Zhu, Hazem Ghoneim, Haitao Wen, Zihai Li, Nuo Sun, Gang Xin.
      Optimal activation of CD8+ T cells is crucial for immunity-mediated destruction of cancer, requiring a substantial amount of proteins involved in metabolism, proliferation, and effector function. Despite extensive studies emphasizing the role of transcriptional regulation in this process, paired transcriptomic and proteomic analyses reveal that the RNA profile is poorly correlated with protein levels. This discrepancy underscores the importance of post-translational modifications (PTMs) in controlling protein abundance during activation. However, the impact of PTMs on the CD8+ T cell protein dynamic remains underexplored. We identify that neddylation, a recently discovered PTM, is activated in response to T cell receptor (TCR) stimulation and enriched in effector CD8+ T cells from colon cancer patients. Mechanistically, we found the rate-limiting enzyme of neddylation, neural precursor cell expressed developmentally down-regulated protein 8 activating enzyme E1 (NAE1), is induced by the NFATc1, a critical transcription factor downstream of TCR signaling. Our observation revealed that genetic ablation of NAE1 significantly disturbed the proteomic landscape related to activation and mitochondrial function. As a result, CD8+ T cells lacking NAE1 exhibited severely compromised activation, proliferation, and survival, which was accompanied by impaired mitochondrial function. Consistently, deletion of NAE1 in CD8+ T cells abolished their antitumor function and promoted tumor progression. By contrast, the overexpression of NAE1 significantly improved the function of tumor-infiltrating CD8+ T cells. Overall, we uncovered neddylation, a previously underappreciated PTM, as a proteomic checkpoint for CD8+ T cell activation. Enforced expression of NAE1 offers promising therapeutic potential for boosting the antitumor CD8+ T cell responses.
    Keywords:  T cells; immunotherapy; post-translational modifications
    DOI:  https://doi.org/10.1073/pnas.2424061122
  8. Cancer Immunol Res. 2025 Mar 12.
    IL-15 complex enhances agonistic anti-CD40 + anti-PDL1 by correcting the T-bet to Tox ratio in CD8+ T cells infiltrating pancreatic ductal adenocarcinoma.
    Zoe C Schmiechen, Hezkiel A Nanda, Adam L Burrack, Grant H Hickok, Jonah Z Butler, Eduardo Cruz-Hinojoza, Nicholas J Maurice, Michael J Geuenich, Chengxin Yu, Alexander K Tsai, Cara-Lin Lonetree, Madeline A Ellefson, Audrey L Hilk, Brandon M Larsen, Ebony A Miller, Antonio B Rizzo, Kieran R Campbell, Steven S Shen, Ingunn M Stromnes.
      Agonistic anti-CD40 with anti-PD-1 can elicit objective responses in a small number of patients with pancreatic ductal adenocarcinoma (PDA). Better understanding of their individual effects on the PDA tumor microenvironment will help inform new strategies to further improve outcomes. Herein, we map tumor-specific CD8+ T-cell differentiation following agonistic anti-CD40 and/or anti-PDL1 in PDA. Rare Tcf1+Slamf6+ CD8+ T cells (TSTEM) are shown to seed memory precursors that transition into a continuum of exhausted and effector T cells. In tumors, anti-PDL1 drove the clonal expansion of Gzmk+ progenitor exhausted (CD8+ T cells, whereas anti-CD40 promoted CD4+ T-cell clonal expansion and accumulation of CD8+ TTSTEM. Cloning the most frequent intratumoral T-cell receptors (TCRs) revealed identical neoepitope specificity, yet the top TCRs from anti-PDL1  anti-CD40 cohorts lacked tetramer binding suggesting lower affinity. Anti-CD40 + anti-PDL1 markedly drove the clonal hyperexpansion of a unique exhausted T-cell (TEX) subset in spleen. TEX were enriched for IL2R, and provision of IL-15 complex (IL-15C) mitigated systemic and intratumoral T-cell exhaustion when combined with anti-CD40 + anti-PDL1, resulting in enhanced antitumor effects, prolongation of animal survival, and resistance to orthotopic tumor rechallenge. Mechanistically, while anti-CD40 + anti-PDL1 mitigated Tox, IL-15C + anti-CD40 + anti-PDL1 increased T-bet thereby conferring a higher T-bet:Tox ratio in tumor-specific CD8+ T cells. Collectively, agonistic anti-CD40 and anti-PDL1 drove systemic and intratumoral CD8+ T-cell clonal expansion and acquisition of exhaustion features. Provision of IL-15C altered the trajectory of T-cell differentiation induced by immunotherapy, resulting in PDA eradication and long-lived antitumor memory T cells.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-24-0758
  9. Immun Ageing. 2025 Mar 08. 22(1): 10
    CD31 + naïve T cells associate with immunosenescence and responsiveness to multiple vaccines in older adults.
    Alper Cevirgel, Martijn Vos, Elske Bijvank, Josine van Beek, Marieke van der Heiden, Anne-Marie Buisman, Debbie van Baarle.
       BACKGROUND: The T cell compartment undergoes significant age-related changes, contributing to the decline of the adaptive immune system and increasing the risk of suboptimal antibody responses to vaccines in older adults. To better understand the association between T cell phenotypes and vaccine responsiveness, we conducted an in-depth analysis of CD4+, CD8+, and γδ + T cells on VITAL cohort participants who are low or high responders to multiple vaccines (influenza, pneumococcal, and SARS-CoV-2).
    RESULTS: Using spectral cytometry and FlowSOM, we identified detailed phenotypes of naïve, regulatory, and terminally differentiated T cells. We observed that the percentages of CD31 + naïve CD4+, CD31 + naïve CD8+, and CD38 + naïve CD8 + T cells were significantly lower in low vaccine responders. Notably, CD31 + naïve T cell subsets showed a stronger correlation with immune entropy, a measure of cumulative immune system perturbations, than with age itself.
    CONCLUSIONS: These findings suggest that subsets of naïve cells could be associated with weak vaccine responsiveness and immunosenescence. Furthermore, these naive T cell signatures could help predict weak vaccine responses, potentially informing targeted vaccination strategies in older adults.
    CLINICAL TRIAL NUMBER: EudraCT: 2019-000836-24.
    DOI:  https://doi.org/10.1186/s12979-025-00504-0
  10. Eur J Immunol. 2025 Mar;55(3): e202451565
    Age and Latent Cytomegalovirus Infection Do Not Affect the Magnitude of De Novo SARS-CoV-2-Specific CD8+ T Cell Responses.
    Jet van den Dijssel, Veronique A L Konijn, Mariël C Duurland, Rivka de Jongh, Lianne Koets, Barbera Veldhuisen, Hilde Raaphorst, Annelies W Turksma, Julian J Freen-van Heeren, Maurice Steenhuis, Theo Rispens, C Ellen van der Schoot, S Marieke van Ham, Rene A W van Lier, Klaas P J M van Gisbergen, Anja Ten Brinke, Carolien E van de Sandt.
      Immunosenescence, age-related immune dysregulation, reduces immunity upon vaccinations and infections. Cytomegalovirus (CMV) infection results in declining naïve (Tnaïve) and increasing terminally differentiated (Temra) T cell populations, further aggravating immune aging. Both immunosenescence and CMV have been speculated to hamper the formation of protective T-cell immunity against novel or emerging pathogens. The SARS-CoV-2 pandemic presented a unique opportunity to examine the impact of age and/or CMV on the generation of de novo SARS-CoV-2-specific CD8+ T cell responses in 40 younger (22-40 years) and 37 older (50-66 years) convalescent individuals. Heterotetramer combinatorial coding combined with phenotypic markers were used to study 35 SARS-CoV-2 epitope-specific CD8+ T cell populations directly ex vivo. Neither age nor CMV affected SARS-CoV-2-specific CD8+ T cell frequencies, despite reduced total CD8+ Tnaïve cells in older CMV- and CMV+ individuals. Robust SARS-CoV-2-specific central memory CD8+ T (Tcm) responses were detected in younger and older adults regardless of CMV status. Our data demonstrate that immune aging and CMV status did not impact the SARS-CoV-2-specific CD8+ T cell response. However, SARS-CoV-2-specific CD8+ T cells of older CMV- individuals displayed the lowest stem cell memory (Tscm), highest Temra and PD1+ populations, suggesting that age, not CMV, may impact long-term SARS-CoV-2 immunity.
    Keywords:  CMV; COVID‐19; aging; antigen‐specific CD8+ T cells; immunosenescence
    DOI:  https://doi.org/10.1002/eji.202451565
  11. J Immunol. 2025 Feb 23. pii: vkae037. [Epub ahead of print]
    MyD88 determines T cell fate through BCAP-PI3K signaling.
    Abraham L Bayer, Zoie Magri, Hayley Muendlein, Alexander Poltorak, Pilar Alcaide.
      The life cycle of effector T cells is determined by signals downstream of the T cell receptor (TCR) that induce activation and proinflammatory activity, or death as part of the process to resolve inflammation. We recently reported that T cell myeloid differentiation primary response 88 (MyD88) tunes down TCR activation and limits T cell survival in the cardiac and tumor inflammatory environments, in contrast to its proinflammatory role in myeloid cells upon toll-like receptor (TLR) recognition of pathogen- and damage-associated molecular patterns. However, the molecular mechanism remains unknown. Here, we report a central regulatory role for MyD88 in T cell apoptosis after TCR activation and Fas ligation through an association with the B cell adaptor for phosphoinositide 3-kinase (B cell activating protein [BCAP]). We show that TCR engagement upregulates MyD88 and BCAP and promotes their interaction, thereby limiting availability of BCAP for downstream TCR-BCAP-PI3K-AKT signaling required for T cell activation and survival, which are enhanced in MyD88-/- activated T cells. Further, MyD88 and BCAP association and localization to the TCR was prevented by lipopolysaccharide (LPS) activation of TLR4 and restored T cell survival in wild-type cells. The enhanced T cell activation markers, proinflammatory signals, and survival advantage observed in MyD88-/- T cells was fully eliminated upon BCAP knockdown in T cells. Our data demonstrate that MyD88 acts downstream of the TCR to regulate T cell fate through its association with BCAP and elucidate a novel molecular mechanism for MyD88 in T cell biology that could be targeted to fine-tune T cell effector function and survival therapeutically.
    Keywords:  T cell receptors; T cells; apoptosis; cell activation; signal transduction
    DOI:  https://doi.org/10.1093/jimmun/vkae037
  12. J Exp Med. 2025 May 05. pii: e20241148. [Epub ahead of print]222(5):
    Transient inhibition of type I interferon enhances CD8+ T cell stemness and vaccine protection.
    Benjamin J Broomfield, Chin Wee Tan, Raymond Z Qin, Hanna Abberger, Brigette C Duckworth, Carolina Alvarado, Lennard Dalit, Chee Leng Lee, Rekha Shandre Mugan, Zihnil A I Mazrad, Hiromi Muramatsu, Liana Mackiewicz, Bailey E Williams, Jinjin Chen, Asuka Takanashi, Stewart Fabb, Marc Pellegrini, Kelly L Rogers, Woohyun J Moon, Colin W Pouton, Melissa J Davis, Stephen L Nutt, Norbert Pardi, Verena C Wimmer, Joanna R Groom.
      Developing vaccines that promote CD8+ T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1+ stem cell-like memory CD8+ T (TSCM) cells are important determinants of long-lived memory. Yet, the developmental requirements for TSCM cell formation are unclear. Here, we identify the temporal window for type I interferon receptor (IFNAR) blockade to drive TSCM cell generation following viral infection and mRNA-lipid nanoparticle vaccination. We reveal a reversible developmental trajectory where transcriptionally distinct TSCM cells emerged from a transitional precursor of exhausted T cellular state concomitant with viral clearance. TSCM cell differentiation correlated with T cell retention within the lymph node paracortex due to disrupted CXCR3 chemokine gradient formation. These effects were linked to increased antigen load and a counterintuitive increase in IFNγ, which controlled cell location. Vaccination with the IFNAR blockade promoted TSCM cell differentiation and enhanced protection against chronic infection. These findings propose an approach to vaccine design whereby modulation of inflammation promotes memory formation and function.
    DOI:  https://doi.org/10.1084/jem.20241148
  13. Cell Rep. 2025 Mar 11. pii: S2211-1247(25)00184-6. [Epub ahead of print]44(3): 115413
    Distinctive CD8+ T cell activation by antigen-presenting plasmacytoid dendritic cells compared to conventional dendritic cells.
    Renée M van der Sluis, Juan L García-Rodríguez, Ian Helstrup Nielsen, Albert Gris-Oliver, Jennifer Becker, Bibiana Costa, M Zeeshan Chaudhry, Marvin Werner, Anders Laustsen, Jesper G Pedersen, Kristine R Gammelgaard, Trine H Mogensen, Ulrich Kalinke, Luka Cicin-Sain, Rasmus O Bak, Lasse S Kristensen, Martin R Jakobsen.
      Plasmacytoid dendritic cells (pDCs) play a pivotal role in immune responses, particularly against viral infections. pDCs exhibit diverse functions, including interferon production, cytokine secretion, and antigen presentation. Here, we investigate the antigen cross-presentation capacity of pDCs and their role in CD8+ T cell activation. Utilizing a culturing system with CD8+ T cells and autologous pDCs derived from circulating CD34+ hematopoietic stem and progenitor cells, we demonstrate that pDCs efficiently activate CD8+ T cells via cross-presentation, promoting T cell expansion and cytotoxic activity. The antigen presentation capacity of pDCs is comparable to that of monocyte-derived dendritic cells (moDCs) and myeloid dendritic cells, which are known for their efficient antigen-presentation capacity. Transcriptomic analysis reveals genetic signatures in CD8+ T cells activated by pDCs distinct from moDCs, suggesting different activation mechanisms. These findings underscore the importance of pDCs in antigen presentation and their contribution to CD8+ T cell activation.
    Keywords:  CD8(+) T cell; CP: Immunology; IFNa; antigen presentation; dendritic cell; immunity; inflammation; pDC; plasmacytoid dendritic cell
    DOI:  https://doi.org/10.1016/j.celrep.2025.115413
  14. Cancer Cell. 2025 Mar 12. pii: S1535-6108(25)00078-9. [Epub ahead of print]
    Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies.
    Housaiyin Li, Dan P Zandberg, Aditi Kulkarni, Simion I Chiosea, Patricia M Santos, Brian R Isett, Marion Joy, Gabriel L Sica, Kevin J Contrera, Curtis M Tatsuoka, Matthias Brand, Umamaheswar Duvvuri, Seungwon Kim, Mark Kubik, Shaum Sridharan, Fei Tu, Jie Chen, Tullia C Bruno, Dario A A Vignali, Anthony R Cillo, Riyue Bao, Jing Hong Wang, Lazar Vujanovic, Robert L Ferris.
      We leverage a clinical trial (NCT04080804) that compared neoadjuvant anti-PD-1, anti-PD-1+CTLA-4, and anti-PD-1+LAG-3 therapies in head and neck squamous cell carcinoma patients. Combination therapies promote higher pathologic response rates versus monotherapy, and major pathologic response is associated with better survival. To address whether successful immune checkpoint inhibitor (ICI) regimens act through similar or distinct pathways, we robustly and longitudinally characterize transcriptional and proteomic dynamics of CD8+ tumor-infiltrating lymphocytes (TILs) in a clonal manner. Anti-PD-1+LAG-3 reprograms CD8+ TIL with type-I interferon response and exhaustion gene programs into effector memory and resident memory (TEM/TRM). In contrast, anti-PD-1+CTLA-4 activates and expands pre-existing TEM/TRM CD8+ TIL, but does not rejuvenate exhausted phenotypes into T effector cells. Anti-PD-1+LAG-3, but not anti-PD-1+CTLA-4, induces widespread TCR sharing among the different transcriptional states, as well as increased TCR diversity in responding patients. Our data suggest doublet regimen-specific transcriptional and clonal dynamics of tumor-reactive CD8+ T cells.
    Keywords:  CTLA-4; Head and neck cancer; LAG-3; PD-1; T cell dynamics; clinical trial; combination immunotherapy; multispectral imaging; single-cell genomics; tumor immunology
    DOI:  https://doi.org/10.1016/j.ccell.2025.02.026
  15. bioRxiv. 2025 Feb 27. pii: 2025.02.26.640157. [Epub ahead of print]
    Sphingolipid metabolism drives mitochondria remodeling during aging and oxidative stress.
    Adam C Ebert, Nathaniel L Hepowit, Thyandra A Martinez, Henrik Vollmer, Hayley L Singkhek, Kyrie D Frazier, Sophia A Kantejeva, Maulik R Patel, Jason A MacGurn.
      One of the hallmarks of aging is a decline in the function of mitochondria, which is often accompanied by altered morphology and dynamics. In some cases, these changes may reflect macromolecular damage to mitochondria that occurs with aging and stress, while in other cases they may be part of a programmed, adaptive response. In this study, we report that mitochondria undergo dramatic morphological changes in chronologically aged yeast cells. These changes are characterized by a large, rounded morphology, decreased co-localization of outer membrane and matrix markers, and decreased mitochondrial membrane potential. Notably, these transitions are prevented by pharmacological or genetic interventions that perturb sphingolipid biosynthesis, indicating that sphingolipids are required for these mitochondrial transitions in aging cells. Consistent with these findings, we observe that overexpression of inositol phospholipid phospholipase (Isc1) prevents these alterations to mitochondria morphology in aging cells. We also report that mitochondria exhibit similar sphingolipid-dependent morphological transitions following acute exposure to oxidative stress. These findings suggest that sphingolipid metabolism contributes to mitochondrial remodeling in aging cells and during oxidative stress, perhaps as a result of damaged sphingolipids that localize to mitochondrial membranes. These findings underscore the complex relationship between mitochondria function and sphingolipid metabolism, particularly in the context of aging and stress.
    DOI:  https://doi.org/10.1101/2025.02.26.640157
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