bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–04–26
35 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Ionic immune checkpoint blockade through potassium-scavenging hydrogel to potentiate CD8+ T cell-mediated cancer immunotherapy.
  2. PIM1 kinase-regulated cellular metabolism sustains differentiation and function of effector CD8+ T cells during chronic viral infection.
  3. Spatiotemporal Transcriptomics Characterizes Immune Microenvironment During Mouse Liver Aging.
  4. Protocol for metabolic profiling of antigen-specific CD8+ T cells using spectral flow cytometry.
  5. Inflammaging in aged tissues drives remodeling of the CD8+ T cell compartment.
  6. Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment.
  7. Organ injury in systemic autoimmunity is mediated by stem-like CD8+ T cells arising from tissue-draining lymph nodes.
  8. Proteasome-haem-BACH2 axis fuels T cell exhaustion.
  9. Regulatory heme: a mitochondria-to-nucleus messenger of CD8+ T-cell exhaustion.
  10. Loss of the actin remodeling protein Flightless-1 impairs CD8 and regulatory T cell function.
  11. Senescence of T cells and organ aging.
  12. CD28-driven ex vivo generation of stem-like memory CD8+ T cells bypassing CD3/TCR signaling.
  13. Selective elimination of circulating effector CD8 T cells via LTβR blockade separates anti-CD137 efficacy from toxicity.
  14. Redox index and capacity analysis (RICA) reveals NAD biology changes in T cell responses in vitro and ex vivo.
  15. Aging Diminishes Thymic Output, Reduces Naive T Cells, Promotes Memory T-Cell Accumulation, and Impairs Thymic Regeneration.
  16. Effector CD8 T cells show additional weaponry during T cell-mediated allograft rejection.
  17. Homeostatic mature dendritic cells instruct fibroblast specialization via Notch2 signaling to establish T cell niches.
  18. Checkpoint blockade and the stem-like T cell trade-off.
  19. Immunosenescence and human healthspan. Lessons from centenarians.
  20. GZMK expression within activated intratumoral T-cell subsets reflects differentiation efficiency and predicts response to cancer immunotherapy.
  21. The long-lived immune system of centenarians.
  22. Blockade of co-inhibitory receptor immune checkpoint protein TIM3/CD366 augments the anti-cancer activity of CAR-T therapy in solid tumors: An ovarian cancer example.
  23. Glutaminase-mediated glutamate metabolism is critical for maintaining Th17/Treg balance.
  24. Lactate Activates TGF-β/SNAIL Signaling to Drive M2 Macrophage Polarization and CD8+ T Cell Exhaustion in Breast Cancer.
  25. N-glycosylation remodeling in aging: Biomarkers and modulators of biological age across organ systems.
  26. Limited protection against early-life lung murine cytomegalovirus infection results from deficiency of cytotoxic CD8 T cells.
  27. Design principles of the cytotoxic CD8+ T cell response.
  28. Soy isoflavone, Soyaflavone HG, improves low T cell proliferation response in aged BALB/c mice.
  29. Co-administration of Rapamycin with a DNA/MVA SIV Vaccine Improves Memory CD8 T Cell Response.
  30. Nanoparticle-mediated metabolic reprogramming for immune modulation in inflammatory diseases.
  31. Mitochondria at the heart of aging: structure, function, and failure.
  32. Expansion of stemlike HIV-specific CD8+ T cells and limited viral epitope diversity characterize durable posttreatment control of HIV.
  33. Mechanical regulation of metabolism, epigenetics, and their interplay.
  34. CD8+ T Cells in Association with SCD1 Regulate Cervical Cancer and Tumour Microenvironment Correlation Research.
  35. Clathrin-independent endocytosis and retrograde transport in cancer cells tune immune synapse organization and CD8 T cell response.
  1. Biomaterials. 2026 Apr 15. pii: S0142-9612(26)00244-9. [Epub ahead of print]333 124220
    Ionic immune checkpoint blockade through potassium-scavenging hydrogel to potentiate CD8+ T cell-mediated cancer immunotherapy.
    Yang Liu, Xu Zhou, Weilin Li, Bing Feng, Jingshan Sun, Ruzhen Li, Huixia Ma, Lanpeng Li, Feng Zhou, Jianxun Ding, Xuesi Chen.
      Immunotherapy efficacy is constrained by immunosuppressive features of the tumor microenvironment (TME) beyond canonical molecular checkpoints, including emerging extracellular ionic regulatory mechanisms that remain poorly characterized. Here, we identify potassium ion (K+) as a metabolically coupled ionic immune checkpoint that suppresses CD8+ T cell antitumor immunity. Using a murine melanoma model with an elevated-K+ microenvironment, we demonstrate that excess extracellular K+ profoundly impairs CD8+ T cell proliferation, activation, and effector function while promoting functional exhaustion without reducing T cell abundance. Mechanistically, K+-mediated immunosuppression is accompanied by restricted glucose uptake, suppressed glycolytic flux, and impaired mitochondrial fitness, establishing metabolic insufficiency as a key basis for ionic checkpoint-driven T cell dysfunction. To therapeutically target this extracellular and non-molecular suppressive mechanism, we develop a localized K+-depleting strategy by encapsulating the clinically approved potassium-binding agent sodium zirconium cyclosilicate (ZS-9) within a thermosensitive poly (lactide-co-glycolide)-polyethylene glycol-poly (lactide-co-glycolide) (PLGA-PEG-PLGA) hydrogel, forming a peritumoral K+-scavenging depot. This biomaterial platform efficiently remodels the ionic TME, restores CD8+ T cell metabolic fitness and effector function, alleviates T cell exhaustion, and significantly enhances the antitumor efficacy of adoptive cell therapy (ACT). Collectively, this work establishes extracellular ionic modulation as a metabolically grounded immune checkpoint mechanism and highlights biomaterials-based ionic remodeling as a translatable strategy to augment cancer immunotherapy.
    Keywords:  Adoptive cell therapy; Immunomodulatory biomaterials; Ionic immune checkpoint; K(+)-scavenging hydrogel; T cell metabolism
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124220
  2. J Immunol. 2026 Apr 15. pii: vkag062. [Epub ahead of print]215(4):
    PIM1 kinase-regulated cellular metabolism sustains differentiation and function of effector CD8+ T cells during chronic viral infection.
    Ashley K Brown, Hongshen Niu, Jian Shen, Yuqi Zhang, Pedro A S Vaz de Castro, Moujtaba Y Kasmani, Siying Lin, Paytsar Topchyan, Nikita L Mani, Peter J Volberding, Samuel E Weinberg, Weiguo Cui.
      CD8+ T-cell differentiation during chronic viral infection is supported by metabolic reprogramming to meet distinct bioenergetic demands. Early effector CD8+ T-cell differentiation and function are supported by the PI3K-Akt-mTOR pathway, while the differentiation of late exhausted CD8+ T cells remains incompletely understood. We first characterized the metabolic heterogeneity of the progenitor, effector, and exhausted CD8+ T-cell subsets in chronic infection by utilizing the Compass algorithm, which provides metabolic state predictions based on single-cell RNA sequencing data and flux-based analysis. Our analysis revealed metabolic programs distinct to each subset of virus-specific CD8+ T cells. In addition, it is known that the differentiation of progenitor to effector CD8+ T cells depends on IL-21-producing CD4+ T cells. We found that PIM1 kinase, a known regulator of cellular energy metabolism that functions downstream of IL-21 signaling, displays high gene expression in the effector CD8 T-cell subset. Using the lymphocytic choriomeningitis virus clone 13 model of chronic viral infection, we showed that CD8+ T cell-specific deletion of PIM1 kinase impairs the differentiation and cytolytic function of late effector CD8+ T cells. Furthermore, deficiency in PIM1 kinase reduced oxidative and glycolytic metabolism, potentially contributing to the diminished effector differentiation and function. Overall, these data reveal not only the metabolic heterogeneity of exhausted CD8+ T cells, but also how metabolic regulation through the IL-21-PIM1 axis impacts CD8+ T-cell differentiation.
    Keywords:  CD8 T cells; PIM kinase; metabolism; viral infection
    DOI:  https://doi.org/10.1093/jimmun/vkag062
  3. Aging Cell. 2026 May;25(5): e70482
    Spatiotemporal Transcriptomics Characterizes Immune Microenvironment During Mouse Liver Aging.
    Jiahua Lu, Yuqian Wang, Wenxue Zhao, Zihao Zhao, Zhaoya Gao, Jin Gu, Cheng Li, Jie Cheng.
      The liver is a major metabolic organ, responsible for synthesizing and breaking down diverse metabolites. Recently, the liver's immunological functions have gradually been unveiled: combating pathogens and maintaining tissue homeostasis. Age-related functional alterations in these immune cells emerge as potential drivers of hepatic dysfunction and age-associated pathologies. However, systematic investigations into spatiotemporal immune cell dynamics during liver aging remain limited. To address this gap, we analyzed young and old mouse livers using single-cell/nuclei and spatial transcriptomics, revealing T cells as the immune cell population with the most pronounced transcriptomic alterations, marked by enrichment of exhausted CD8+ T cells in aged livers. Spatial mapping showed exhausted CD8+ T cells accumulating in portal vein (PV) zone, co-localizing with periportal hepatocytes (PP hepatocytes). Up-regulation of LPIN1 in PP hepatocyte promoted T cell exhaustion. CD8+ T cell exhaustion was tightly associated with disease progression. Therefore, our findings suggest that targeting LPIN1 may alleviate T cell exhaustion, offering potential therapeutic strategies for age-related liver diseases.
    Keywords:  T cell exhaustion; aging; liver; single‐cell/nuclei transcriptome; spatial transcriptome
    DOI:  https://doi.org/10.1111/acel.70482
  4. STAR Protoc. 2026 Apr 22. pii: S2666-1667(26)00170-X. [Epub ahead of print]7(2): 104517
    Protocol for metabolic profiling of antigen-specific CD8+ T cells using spectral flow cytometry.
    J Fréderique de Graaf, Nils Mülling, Ramon Arens.
      CD8+ T cells rely on tightly regulated metabolic remodeling to support effector function. Here, we present a protocol for single-cell metabolic profiling of rare antigen-specific CD8+ T cells in unstimulated and antigen-stimulated conditions using spectral flow cytometry. The workflow enables detailed assessment of key metabolic pathways, including glycolysis, fatty acid oxidation, amino acid metabolism, the pentose phosphate pathway, and mitochondrial oxidative phosphorylation. For complete details on the use and execution of this protocol, please refer to Mülling et al.1.
    Keywords:  Cell Biology; Immunology; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2026.104517
  5. Cell Rep. 2026 Apr 22. pii: S2211-1247(26)00381-5. [Epub ahead of print]45(5): 117303
    Inflammaging in aged tissues drives remodeling of the CD8+ T cell compartment.
    Irina Shchukina, Carlos J Rodriguez-Hernandez, Heather S Ruiz, Maksim Kleverov, Rachel L Mintz, Katsutaka Mineura, Subhadra C Gunawardana, Sunnie Hsiung, Bishan Bhattarai, Veronika Vachova, Jan Kossl, Denis A Mogilenko, Rachael L Field, Tran H Nguyen, Quazim A Alayo, Christopher G Huckstep, Barbora Vander Wielen, Jonathan R Brestoff, Sheila A Stewart, David W Piston, Takeshi Egawa, Daniel Kreisel, Gwendalyn J Randolph, Maxim N Artyomov.
      Aging strongly impacts CD8+ T cells, including the loss of naive cells and the emergence of age-associated GZMK+CD8+ T cells (TAA cells). Although TAA cells constitute a major population in aged mice, the pathway underlying their differentiation remains unknown. Here, we demonstrate that TAA cell development is cell extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a TNFΔ69AU/+ mouse model, we show that low-grade inflammation accelerates CD8+ T cell aging and promotes early accumulation of TAA cells. Analysis of TAA cell heterogeneity further identifies a progenitor subpopulation enriched in the aged adipose tissue. Finally, heterochronic transplantation experiments suggest that the aged adipose tissue can serve as a systemic source of TAA cells and contribute to the conversion of young CD8+ T cells into the aged phenotype. Together, these findings indicate that aged non-lymphoid tissues actively drive CD8+ T cell remodeling and identify adipose tissue as an important niche shaping immune aging.
    Keywords:  CD8(+) T cells; CP: immunology; adipose tissue; aging; granzyme K; inflammaging
    DOI:  https://doi.org/10.1016/j.celrep.2026.117303
  6. Aging Cell. 2026 May;25(5): e70510
    Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment.
    Mary P Udumula, Anjaly Km, Faraz Rashid, Mohammad Nematullah, Harshit Singh, Tanya Bhardwaj, Miriana Hijaz, Shailendra Giri, Eduardo N Chini, Heather M Gibson, Ramandeep Rattan.
      Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg) mediated immunosuppression. In aged EOC-bearing mice, we observed reduced survival, accompanied by impaired CD4+ and CD8+ T cell responses and a marked expansion of FOXP3+ Tregs exhibiting elevated IL-10 and TGFβ expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged mice, along with a fivefold increase in intracellular succinate levels. This accumulation of succinate within the aged tumor microenvironment was found to potentiate Treg suppressive function. Notably, pharmacologic inhibition of α-ketoglutarate dehydrogenase reversed this effect, restoring effector T cell activity. These findings highlight succinate-driven metabolic reprogramming as a central mechanism of age-related Treg dysfunction in EOC and suggest that targeting succinate metabolism may offer a promising strategy to rejuvenate antitumor immunity in elderly patients.
    Keywords:  Tregs; aging; immunosuppression
    DOI:  https://doi.org/10.1111/acel.70510
  7. Immunity. 2026 Apr 20. pii: S1074-7613(26)00133-0. [Epub ahead of print]
    Organ injury in systemic autoimmunity is mediated by stem-like CD8+ T cells arising from tissue-draining lymph nodes.
    Accelerating Medicines Partnership: RA/SLE Network
      Although loss of B cell tolerance, autoantibody production, and immune complex deposition are hallmarks of systemic lupus erythematosus (SLE), CD8+ T cell infiltration in the kidneys is the best predictor of poor prognosis in lupus nephritis, a severe manifestation of SLE. Here, we examined the origin, differentiation, and functional consequences of CD8+ T cells infiltrating kidneys in lupus-prone mice. TCF-1+ stem-like CD8+ T cells in renal-draining lymph nodes underwent T cell receptor (TCR)-dependent, antigen-driven expansion with differentiation into cytotoxic kidney-infiltrating cells that promoted tissue injury contingent on CD4+ T cell help and interleukin (IL)-21 and IL-15 signaling. CD8+ T cell differentiation was marked by persistent AP-1 activity and cytotoxic function despite increased expression of immune checkpoints. A parallel program of CD8+ T cell differentiation in the kidneys of patients with lupus nephritis reflected shared pathogenesis. Thus, a T cell differentiation program analogous to that in chronic infections and cancer is found in lupus; however, CD8+ T cells in systemic autoimmunity retain effector function despite terminal differentiation.
    Keywords:  CD4(+) T cells; CD8(+) T cells; SLE; T cell differentiation; autoimmunity; cytotoxicity; lupus nephritis; stem-like T cells; tissue injury
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.022
  8. Trends Immunol. 2026 Apr 23. pii: S1471-4906(26)00095-5. [Epub ahead of print]
    Proteasome-haem-BACH2 axis fuels T cell exhaustion.
    Jiajia Wang, Ziyi Luo, Haitao Shen, Lianjun Zhang.
      It remains unclear how mitochondrial stress instructs the transcriptional programme of terminal T cell exhaustion. In a recent study, Xu et al. uncovered a proteasome-haem-BACH2 axis in which haem liberated from damaged mitochondrial haemoproteins acts as a molecular messenger that couples mitochondrial injury to terminal T cell exhaustion.
    Keywords:  BACH2; T cell exhaustion; mitochondrial stress; proteostasis; regulatory haem
    DOI:  https://doi.org/10.1016/j.it.2026.04.002
  9. Cell Mol Immunol. 2026 Apr 22.
    Regulatory heme: a mitochondria-to-nucleus messenger of CD8+ T-cell exhaustion.
    Hao Song, Hao Shi, Hongbo Chi.
      
    DOI:  https://doi.org/10.1038/s41423-026-01420-z
  10. J Immunol. 2026 Apr 15. pii: vkag019. [Epub ahead of print]215(4):
    Loss of the actin remodeling protein Flightless-1 impairs CD8 and regulatory T cell function.
    Michelle M Lissner, Jenna M Sullivan, Minjian Ni, McKenna Sherve, Anne M Hocking, Jessica A Hamerman, Daniel J Campbell.
      T cell immunity depends on the precise coordination of signaling networks with actin cytoskeleton remodeling, yet the molecular regulators of these processes remain incompletely defined. Flightless-1 (FLII) is a gelsolin-family actin regulator with unique leucine-rich repeats that can couple cytoskeletal dynamics to diverse signaling pathways. Here, using conditional knockout mice, we identify essential roles for FLII in both CD8+ and regulatory T cells. Loss of FLII in CD8+ T cells caused a profound loss of naive cells from the spleen, impaired CCR7-dependent migration, and defective accumulation in the lung parenchyma during antigen-specific responses to respiratory vesicular stomatitis virus infection, despite largely preserved activation, effector differentiation, and cytotoxic function. FLII-deficient Foxp3+ regulatory T cells maintained normal numbers but exhibited diminished CD25 expression, defective interleukin (IL)-2 signaling and failed to restrain spontaneous, tissue-specific autoimmunity. These findings identify FLII as a critical and previously unrecognized orchestrator of T cell trafficking and immune regulation, which may link chemokine receptor signaling to actin remodeling and is essential for proper T cell migration and function.
    Keywords:  CD8+ T cells; Flightless-1; gelsolin; regulatory T cells
    DOI:  https://doi.org/10.1093/jimmun/vkag019
  11. Inflamm Regen. 2026 Apr 24. pii: 19. [Epub ahead of print]46(1):
    Senescence of T cells and organ aging.
    Masaki Ohyagi, Minako Ito, Akihiko Yoshimura.
      Senescence of T cells is strongly linked to organismal aging through two interconnected processes: chronic low-grade inflammation and reduced immune surveillance of senescent cells. T cells are particularly vulnerable to thymic involution, hematopoietic stem cell aging, repeated homeostatic proliferation, chronic antigenic stimulation, and metabolic and mitochondrial dysfunction. As a result, aged T cells may lose their capacity to combat infection and eliminate senescent cells, while also contributing to inflammaging through the production of inflammatory cytokines. Recent preclinical studies in murine models have demonstrated that modulation of T-cell immunosenescence can ameliorate age-related diseases. These approaches include PD-1/PD-L1 blockade, senolytic chimeric antigen receptor T (CAR-T) cells, and CXCL4/platelet factor 4 (PF4). In addition, early-stage human clinical studies of caloric restriction, low-dose mTOR inhibition, thymic regeneration, and mesenchymal stromal/stem cell (MSC) therapy suggest that interventions targeting immunosenescence may provide health benefits. Moreover, in murine models of Alzheimer's disease, T cells infiltrating the brain may exert either disease-promoting or protective effects depending on the disease stage, highlighting an important point of intersection between T-cell-mediated immunosenescence and brain aging. This review summarizes the basic concepts of immunosenescence, the molecular basis of immune surveillance of senescent cells, age-associated T-cell subsets, their links to brain aging, and interventional strategies aimed at clinical translation, with particular emphasis on T-cell biology and the transcriptional regulatory network driven by NR4a.
    Keywords:  Chemokine; Immunosenescence; Inflammaging; NR4a; PD-1/PD-L1; Spatial transcriptomics; T cells
    DOI:  https://doi.org/10.1186/s41232-026-00419-3
  12. Proc Natl Acad Sci U S A. 2026 Apr 28. 123(17): e2524626123
    CD28-driven ex vivo generation of stem-like memory CD8+ T cells bypassing CD3/TCR signaling.
    Fumie Ihara, Yota Ohashi, Evey Y F Zheng, Saori Fukao, Rowena Rodrigo, Babak Noamani, Giselle M Boukhaled, Ben X Wang, Dong-Hoon Han, Xinyu Wei, Brian D Burt, Kayoko Saso, Yukiko Matsunaga, Dalam Ly, Yuki Kagoya, Marcus O Butler, Tak W Mak, Samuel D Saibil, Naoto Hirano.
      Adoptive T cell therapies typically rely on ex vivo CD3/CD28 stimulation, which promotes effector differentiation and limits the persistence of transferred cells. Stem cell-like memory T cells (Tscm), with their capacity for self-renewal and multipotency, represent an ideal therapeutic subset but remain difficult to generate at scale. Here, we present a CD3-independent strategy using artificial antigen-presenting cells expressing a membrane-bound CD28 superagonist (αCD28-aAPCs) to expand CD8+ T cells with Tscm-like features. In naïve CD8+ T cells, αCD28-aAPC stimulation initiates a distinct transcriptional and epigenetic program, marked by high TCF1 expression, metabolic fitness, and resistance to exhaustion-key hallmarks of the Tscm phenotype. Mechanistically, this approach circumvents canonical CD3/TCR signaling and notably avoids induction of IRF4, a key transcription factor that drives BLIMP1 upregulation, TCF1 downregulation, and glycolytic commitment during effector differentiation. Instead, sustained CD28 signaling alone reprograms T cells toward a Tscm-like state. Upon subsequent antigen encounter and CD3 engagement, these αCD28-aAPC-expanded T cells mount robust effector responses while retaining superior persistence and antitumor activity in preclinical models. Our findings reveal an underappreciated role of CD28 signaling in guiding Tscm-like fate through IRF4 suppression and establish a platform for generating durable and functionally potent T cell therapies.
    Keywords:  CD28 signaling; CD3-independent activation; adoptive T cell therapy; artificial antigen-presenting cells; stem cell–like memory T cells
    DOI:  https://doi.org/10.1073/pnas.2524626123
  13. Sci Adv. 2026 Apr 24. 12(17): eaea8737
    Selective elimination of circulating effector CD8 T cells via LTβR blockade separates anti-CD137 efficacy from toxicity.
    Sergey A Shein, Anna A Korchagina, Li-Ju Wang, Zhao Lai, Yidong Chen, Jacob S Fisher, Burkhard Ludewig, Jessica N Lancaster, Yang-Xin Fu, Ekaterina Koroleva, Alexei V Tumanov.
      The major barrier to clinical translation of αCD137 immunotherapy is separating antitumor efficacy from hepatotoxicity driven by IFN-γ-producing CD8 T cells. We propose a strategy to limit toxicity by promoting contraction of excessively expanded CD8 T cells. We identify CD11c+KLRG1+ effector CD8 T cells (CD11c+TE) as the primary source of IFN-γ, recirculating between blood and secondary lymphoid organs (SLOs), where they undergo apoptosis during contraction. We show that lymphotoxin β receptor (LTβR) signaling restrains this contraction. Mechanistically, lymphotoxin-expressing B cells activate LTβR in fibroblastic reticular cells (FRCs), suppressing apoptosis of CD11c+TE cells in the spleen and sustaining their systemic circulation and liver infiltration. Pharmacological LTβR blockade abrogates hepatotoxicity by reducing the accumulation of IFN-γ-producing CD11c+TE cells while preserving tumor-specific CD8 T cell responses. These findings identify LTβR as a key regulator of effector CD8 T cell persistence and support the use of LTβR antagonists to improve the safety of αCD137-based immunotherapy.
    DOI:  https://doi.org/10.1126/sciadv.aea8737
  14. J Immunol. 2026 Apr 15. pii: vkag035. [Epub ahead of print]215(4):
    Redox index and capacity analysis (RICA) reveals NAD biology changes in T cell responses in vitro and ex vivo.
    Alicia M Bostwick-Galaviz, Edward J Usherwood.
      The importance of NAD metabolism in T cell differentiation and function has gained attention in recent years. However, technical limitations impede the specific interrogation of NAD dynamics in living immune cells. In this report, we present the redox index and capacity analysis (RICA) assay, a novel technique for measuring mitochondrial NAD content and redox balance. The RICA assay is a flow cytometry-based technique that uses NADH autofluorescence and mitochondrial inhibitors to assess NAD within specific phenotypic subsets of immune cells. We validated this technique using metabolic modulators and used it to examine murine CD8 T cell subsets in vitro and ex vivo. Consistent with previous findings, we observed that metabolically active, effector-like cells had a higher mitochondrial NADH:NAD+ ratio than quiescent cells. We discovered that cells with greater differentiation potential often possessed a larger pool of mitochondrial NAD than terminally differentiated cells in vitro and in a vaccinia viral immunization model. Mitochondrial NAD content fluctuated considerably in response to fuel availability and metabolic modulators, even within short treatment timeframes. Finally, tumor localization and differentiation status dramatically affected the mitochondrial NAD pool but not the NADH:NAD+ ratio of adoptively transferred CD8 T cells in a B16 melanoma model. This study establishes a tool for evaluating mitochondrial NAD biology in living immune cells at a greater level of detail than previously possible. It also highlights dynamic changes in mitochondrial NAD pool size as an important and novel element of CD8 T cell biology.
    Keywords:  NAD; T cells; cancer; techniques
    DOI:  https://doi.org/10.1093/jimmun/vkag035
  15. Am J Physiol Regul Integr Comp Physiol. 2026 Apr 24.
    Aging Diminishes Thymic Output, Reduces Naive T Cells, Promotes Memory T-Cell Accumulation, and Impairs Thymic Regeneration.
    Daria M Konovalova, Madison D Cooper, Shuli Huang, Danielle X Shane, Jordyn S Mulhern, Ying Ann Chiao, Sarah Y Yuan, Yonggang Ma.
      Aging increases susceptibility to a wide range of diseases, partially due to alterations in T lymphocytes. This study aimed to characterize age-related changes in T-cell output, phenotype, and function under basal conditions and after myocardial infarction (MI). Compared with young mice (2-6 months), aged mice (≥18 months) demonstrated reduced thymic size and fewer developing thymocytes. Accordingly, circulating T-cell counts were significantly lower in aged mice than in young mice. Interestingly, the spleen and bone marrow of aged mice showed increased T-cell accumulation, primarily due to expansion of memory T cells. Similarly, older humans (≥60 years old) exhibited reduced circulating T cells and a higher proportion of memory T cells. Under basal conditions, aged splenic T cells expressed higher mRNA levels of pro-inflammatory and cytotoxic factors (e.g. Ifnγ, Tnfα, granzyme b, and perforin). Moreover, aged T cells exhibited a higher frequency of PD-1+, TIGIT+, LAG-3+, and CTLA-4+ cells compared to young T cells, indicative of an exhausted phenotype. Metabolically, aged T cells showed higher basal glycolytic and mitochondrial oxidative phosphorylation. Following MI, thymic regeneration was evident in young mice by day 14, whereas the aged thymus remained atrophic. Additionally, aged MI mice exhibited reduced naïve T cells and increased memory T cells in the spleen and bone marrow than young mice. In conclusion, our study reveals that aging diminishes thymocyte output and circulating T-cell pools, facilitates memory T-cell accumulation, and compromises thymic regeneration under basal conditions and post-MI.
    Keywords:  T cells; aging; bone marrow; myocardial infarction; thymus
    DOI:  https://doi.org/10.1152/ajpregu.00242.2025
  16. Mol Ther. 2026 Apr 17. pii: S1525-0016(26)00268-6. [Epub ahead of print]
    Effector CD8 T cells show additional weaponry during T cell-mediated allograft rejection.
    Robert L Fairchild.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2026.04.007
  17. Immunity. 2026 Apr 23. pii: S1074-7613(26)00134-2. [Epub ahead of print]
    Homeostatic mature dendritic cells instruct fibroblast specialization via Notch2 signaling to establish T cell niches.
    Nagham Alouche, Hélène Cannelle, Stéphanie Favre, Marija Jokić, José A Villegas, Sandra Maréchal, Clint De Nolf, Maeva Delacrétaz, Alexandros Sifis, Chloé Chapuis, Allison Burns, Giovanna Ambrosini, Isabelle Dupanloup, Jun Abe, Ute Koch, Nicolas Guex, Jens V Stein, Ivan Maillard, Tom Cupedo, Burkhard Ludewig, Freddy Radtke, Sophie Janssens, Sanjiv A Luther.
      Compartmentalization of secondary lymphoid organs is orchestrated by specialized fibroblastic reticular cells (FRCs), which guide immune cell migration, interaction, and function. Here, we investigated the pathways driving FRC differentiation into functionally distinct subsets. A Notch signaling signature distinguished lymph node (LN) FRCs, and deletion of Notch1 and Notch2 in FRCs restricted functional specialization, particularly for T-zone FRCs (T-zone reticular cells [TRCs]). Dendritic cell (DC)-specific deletion of the Notch ligand Jagged-1 prevented Ccl19hi TRC differentiation, with homeostatic Ccr7+ DCs also being required for their maintenance. The resulting Ccl19 chemokine expression supported formation of central T-zone sub-compartments enriched in Xcr1+ DCs and CD8+ T cells. Both the spatial organization and Notch2-Jagged1 signaling activity were conserved in human LNs. Disrupting T-zone segregation via Notch2 inactivation in FRCs impaired the generation of CD8+ T cell memory precursors. Thus, Notch2-dependent TRC programming by DCs shapes distinct T-zone niches that sustain CD8+ T cell immunity.
    Keywords:  CD8+ T memory precursor cells; Ccl19; Ccr7; Notch signaling; T cell zone; compartmentalization; dendritic cells; fibroblastic reticular cells; homeostasis; lymph node; secondary lymphoid organs
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.023
  18. Mol Oncol. 2026 Apr 20.
    Checkpoint blockade and the stem-like T cell trade-off.
    Julie M Mazet, Johanna A Joyce.
      Stem-like T cells are central to the efficacy of programmed cell death protein 1 (PD1) blockade, sustaining long-term immune responses by serving as a renewable reservoir for anti-tumor effector CD8+ T cells. However, the mechanisms governing their maintenance and regulation in cancer remain incompletely understood. Addressing this gap, Hor et al. combined high-dimensional 3D-imaging with immunological profiling to define the niche of stem-like T cells within tumor-draining lymph nodes in murine cancer models. Their study identifies a critical role for conventional type 1 dendritic cells (cDC1s) and the PD1 pathway in preserving high-affinity tumor-specific stem-like T cells. cDC1s deliver sustained T-cell receptor (TCR) stimulation together with PD-L1/2 co-inhibitory signals that support stemness, proliferation, and survival. Strikingly, disruption of PD1 signaling transiently enhances effector T cell expansion but promotes differentiation and apoptosis of stem-like T cells, ultimately depleting this essential pool. These findings reveal a potential long-term vulnerability of immune checkpoint blockade, particularly when tumors are not eradicated during the initial treatment response.
    Keywords:  Stem‐like T cells; cancer immunity; immune checkpoint blockade
    DOI:  https://doi.org/10.1002/1878-0261.70257
  19. Curr Opin Immunol. 2026 Apr 16. pii: S0952-7915(26)00054-3. [Epub ahead of print]100 102777
    Immunosenescence and human healthspan. Lessons from centenarians.
    Juan-Manuel Anaya, Ivan D Lozada-Martinez, Yeny Acosta-Ampudia, Gabriel Tobón.
      Immunosenescence is a multidimensional remodeling of immunity, characterized by inflammaging, cellular senescence, T-cell exhaustion, and thymic involution, that raises infection and disease risk with age. Emerging evidence, notably from centenarians, shows immune aging follows divergent trajectories: rather than a uniform decline, extreme longevity often reflects adaptive remodeling and a maintained immune equilibrium. Centenarian immune profiles are characterized by selective retention of naïve T cells, expansion of cytotoxic CD4+ and CD8+ subsets, tightly regulated inflammatory signaling, and systemic protective mechanisms such as enhanced oxidative-stress resistance, preserved epigenetic regulation, and extracellular vesicle-mediated T-cell modulation. Progress is constrained by cohort heterogeneity and limited longitudinal, harmonized multi-omic data; addressing these gaps could produce biological-age biomarkers and inform immunometabolic or senotherapeutic strategies to extend healthspan. In this narrative review, we describe that immunosenescence should be viewed as a trajectory-dependent process in which balanced immune function, not mere preservation of youthful markers, determines resilience and healthy aging.
    DOI:  https://doi.org/10.1016/j.coi.2026.102777
  20. NPJ Precis Oncol. 2026 Apr 18.
    GZMK expression within activated intratumoral T-cell subsets reflects differentiation efficiency and predicts response to cancer immunotherapy.
    Cem M Sievers, Tian-Gen Chang, Yvette Robbins, Jay Friedman, Marco Craveiro, Xinping Yang, Christopher Silvin, Jason M Redman, Patrick Soon-Shiong, Wiem Lassoued, Martha Quezado, Wojciech Mydlarz, Nancy P Judd, Jeffrey Schlom, James Gulley, Eytan Ruppin, Clint T Allen.
      Neoadjuvant immunotherapies (NITs) have demonstrated clinical benefit in head and neck carcinoma and other cancers by enhancing T cell-mediated anti-tumor immunity. However, disease recurrence remains a major challenge in a significant proportion of patients. Characterization of T cell dynamics underlying NIT outcomes may lead to improved treatment strategies. Here, we identify baseline intratumoral T cell differentiation efficiency as a predictor of response to NIT. Clonal analysis of tumor-emergent T cells post-treatment revealed granzyme K (GZMK) expression within differentiated subsets as a marker of recent differentiation. Efficient pre-treatment differentiation of GZMK+ progenitor T cells toward activated effectors predicts increased treatment-induced tumor regression. Consistently, pre-treatment tumor-infiltrating T cell clones predominantly adopt either exhausted, tissue-resident memory-like, or peripherally enriched GZMK+ progenitor states, implicating impaired intratumoral differentiation in limited anti-tumor immunity at baseline. Together, our findings demonstrate that GZMK+ T cell profiles reflect baseline anti-tumor immunocompetence and offer a clinically actionable biomarker for predicting immunotherapy response. NCT04247282, ClinicalTrails.gov, registered 1/30/2020 and NCT03429036, ClinicalTrails.gov, registered 11/06/2020.
    DOI:  https://doi.org/10.1038/s41698-026-01437-7
  21. Nat Rev Immunol. 2026 Apr 23.
    The long-lived immune system of centenarians.
    Abel Plaza-Florido, Pedro Carrera-Bastos, Inmaculada Pérez-Prieto, Carmen Fiuza-Luces, Shlomit Radom-Aizik, Borja Del Pozo Cruz, Claudio Franceschi, Alejandro López-Soto, Carlos López-Otín, Alejandro Lucia.
      Centenarians - individuals aged 100 years or older - constitute a biologically distinct human population that achieves exceptional longevity while frequently retaining functional independence and avoiding major age-related diseases or postponing their onset. Despite their advanced age, many centenarians show relatively preserved immune function and resistance to conditions linked to immunosenescence and chronic low-grade inflammation (inflammageing). These features are especially pronounced in semi-supercentenarians (105-109 years) and supercentenarians (≥110 years), whose immune profiles often resemble those of much younger individuals. In this Review, we explore how centenarians modulate key hallmarks of immune ageing across innate and adaptive immune compartments. We discuss evidence that they limit the pathological effects of inflammageing, potentially through reduced NLRP3 inflammasome activation, enhanced autophagy and a tempered senescence-associated secretory phenotype. Omics studies further reveal transcriptomic, epigenetic and microbial signatures consistent with preserved immune function, including youth-like gene expression patterns in circulating immune cells and beneficial shifts in gut microbiome composition. Together, these findings suggest that centenarians achieve longevity through coordinated adaptations that maintain immune homeostasis and disease resistance and may inform strategies to enhance healthspan in ageing societies.
    DOI:  https://doi.org/10.1038/s41577-026-01291-5
  22. Genes Dis. 2026 Jul;13(4): 101978
    Blockade of co-inhibitory receptor immune checkpoint protein TIM3/CD366 augments the anti-cancer activity of CAR-T therapy in solid tumors: An ovarian cancer example.
    Binglan Zhang, Fuping Zhu, Song Wang, Yong Huang, Shishi Yu, Shaorong Tian, Minmin Li, Pan Li, Qian Xue, Bingqiang Zhang.
      Strategies that enhance the function of chimeric antigen receptor-modified T (CAR-T) cells for solid tumors are critical. Inhibitory immuno-checkpoints blockade could potentially enhance CAR-T cell function. TIM-3 is an important negative regulator of T cell activity, but whether TIM-3 blockade could affect CAR-T cell function remains unclear. In our study, we successfully constructed TIM-3-silenced CAR-T cells by dual-promoter lentivirus vectors that simultaneously express the TIM-3 targeting short hairpin RNA (shRNA) and a third-generation CAR recognizing HER2. We demonstrated that down-regulation of TIM-3 did not affect the phenotype of CAR-T cells. CAR-T cells with TIM-3 blockade exhibited higher lytic cytotoxicity to target cells in vitro. Additionally, TIM-3-silenced CAR-T cells displayed robust anti-tumor activity in a murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates the effect of down-regulation of immune checkpoint TIM-3 on the anti-tumor function of CAR T cells, providing new ideas for improving the potency of CAR-T cell therapies in solid tumors.
    Keywords:  Cell therapy; Chimeric antigen receptor; Immunotherapy; Inhibitory checkpoint; TIM-3
    DOI:  https://doi.org/10.1016/j.gendis.2025.101978
  23. Cent Eur J Immunol. 2025 ;50(4): 341-352
    Glutaminase-mediated glutamate metabolism is critical for maintaining Th17/Treg balance.
    Xiaohan Jin, Jinglong Tao.
      Autoimmune diseases are severe disorders that affect populations worldwide. Their occurrence is considered to be multifactorial: genetic, hormonal and immunological factors all contribute to the development of autoimmune diseases. CD4 T cells differentiate into different subtypes, among which Th17 and Treg cells are the two most important in regulation of immune response balance. The Th17/Treg equilibrium is crucial in the pathogenesis of autoimmune diseases. Glutamate, an excitatory neurotransmitter in the nervous system, induces multiple effects. It activates normal T cells, enhancing cell adhesion, migration, secretion and gene expression. However, the effect of glutamate on T cell fate remains unclear. Here, we found that glutamate promotes Treg differentiation but suppresses Th17 differentiation. Further results showed that the rate-limiting enzyme of glutamate metabolism, glutaminase (GLS), is the key regulator for Treg cell generation. These findings suggest that GLS-mediated glutamate metabolism is critical for Treg cell differentiation, and may represent a potential therapeutic target for autoimmune disease.
    Keywords:  Th17; Treg; autoimmune; glutaminase; glutamine
    DOI:  https://doi.org/10.5114/ceji.2025.155429
  24. FASEB J. 2026 Apr 30. 40(8): e71753
    Lactate Activates TGF-β/SNAIL Signaling to Drive M2 Macrophage Polarization and CD8+ T Cell Exhaustion in Breast Cancer.
    Peiling Zhu, Zhisheng Tian, Ying Wang, Haiying Liao, Zehui Mi.
      This study demonstrates that lactate promotes M2-like macrophage polarization by activating the TGF-β/SNAIL signaling axis, thereby weakening CD8+ T cell-mediated antitumor immunity and promoting breast cancer progression. In vitro experiments using bone marrow-derived macrophages (BMDMs) and THP-1 cells treated with 25 mM lactate revealed a marked increase in M2 markers (CD206, Arg-1, IL-10) and a reduction in M1 markers (iNOS, TNF-α, IL-12), confirmed by Western blotting and flow cytometry. RNA-Seq analysis identified TGF-β/SNAIL pathway activation, with increased TGFBR1/2 expression, Smad2/3 phosphorylation, and PI3K/AKT pathway enrichment. Functional studies revealed that lactate-polarized M2 macrophages impaired CD8+ T cell cytotoxicity (reduced IFN-γ, GzmB, PRF1; elevated PD-1, Tim-3) and disrupted mitochondrial metabolism. In vivo validation using a breast cancer xenograft model showed that lactate treatment increased tumor growth and angiogenesis (VEGF/CD31+), while TGF-β inhibition (SB431542) reversed these effects. Mechanistically, lactate-induced TGF-β/SNAIL signaling promoted EMT in cancer cells and created an immunosuppressive TME. These findings establish lactate as a critical metabolic regulator that coordinates macrophage polarization and T cell exhaustion through the TGF-β/SNAIL axis, highlighting this pathway as a promising therapeutic target for breast cancer immunotherapy.
    Keywords:  CD8+ T Cells; M2 polarization; SNAIL; breast cancer; lactate; transforming growth factor‐beta
    DOI:  https://doi.org/10.1096/fj.202502538RR
  25. Biochim Biophys Acta Gen Subj. 2026 Apr 22. pii: S0304-4165(26)00050-4. [Epub ahead of print]1870(7): 130950
    N-glycosylation remodeling in aging: Biomarkers and modulators of biological age across organ systems.
    Aswath Balakrishnan, Blake Krisko, Christofer Daniel Sánchez, Haik Mkhikian.
      Aging is characterized by progressive functional decline, increased disease susceptibility, and dysregulation of cellular homeostasis. Among post-translational modifications, N-glycosylation has emerged as a key regulator of protein stability, signaling, and immune function with broad relevance to aging biology. Recent large-scale glycomic studies demonstrate that the human N-glycome undergoes consistent age-associated remodeling across plasma, immune cells, and tissues, including reduced galactosylation and sialylation, altered fucosylation, and changes in N-glycan branching. These shifts are particularly pronounced on immunoglobulin G (IgG), where Fc N-glycan profiles serve as robust biomarkers of biological age, inflammation, morbidity, and mortality risk. Beyond circulating markers, cell and tissue-specific analyses reveal that regulated changes in glycosylation directly influence receptor signaling, inflammatory tone, and organ level aging phenotypes in the cardiovascular, nervous, and immune systems. Mechanistically, age-dependent N-glycan remodeling reflects the integrated effects of transcriptional reprogramming of glycosyltransferase networks, metabolic regulation of nucleotide sugar availability, and altered spatial organization of glycosylation enzymes within the Golgi apparatus. Importantly, emerging evidence indicates that plasma N-glycosylation patterns are partially reversible through metabolic and lifestyle interventions. Together, these findings position N-glycosylation as a central and dynamic component of aging biology, linking metabolic and inflammatory states to functional outcomes across biological scales.
    Keywords:  Aging; Glycan clock; Inflammaging; N-glycosylation; Plasma glycome; T cell dysfunction
    DOI:  https://doi.org/10.1016/j.bbagen.2026.130950
  26. PLoS Pathog. 2026 Apr 20. 22(4): e1014150
    Limited protection against early-life lung murine cytomegalovirus infection results from deficiency of cytotoxic CD8 T cells.
    Luís Fonseca Brito, Eleonore Ostermann, Silvia Tödter, Sanamjeet Virdi, Daniela Indenbirken, Renke Brixel, Ramon Arens, Adam Grundhoff, Wolfram Brune, Felix Rolf Stahl.
      Differential antiviral T cell immunity in early life impacts the clinical outcome of Cytomegalovirus (CMV) infection, but the underlying mechanisms are not well understood. T cells are known to be involved in protection from CMV disease. To further elucidate these mechanisms, we used a model of respiratory murine CMV (MCMV) infection and adoptive T cell transfers to characterize MCMV-specific T cell responses in early life. We analyzed the effector T cell differentiation using single-cell RNA sequencing and assessed the local pulmonary cytokine milieu. We found delayed enrichment of early-life murine MCMV-specific CD8 T cells due to a general deficiency of αβ T cells. Adoptive transfer of naïve adult T cells into neonates did not protect from lung MCMV infection due to generation of non-cytotoxic CD8 effector T cells. Furthermore, key cytokines required for effective CD8 T cell priming were absent in early life. Supplementation with these cytokines enhanced infection control by transferred adult T cells. The effector function of adult-primed T cells was not disrupted in neonates. Together, this study suggests defective CD8 T cell priming in neonates as a factor explaining the higher risk for MCMV lung disease in the early-life phase.
    DOI:  https://doi.org/10.1371/journal.ppat.1014150
  27. Proc Natl Acad Sci U S A. 2026 Apr 28. 123(17): e2528202123
    Design principles of the cytotoxic CD8+ T cell response.
    Obinna A Ukogu, Zachary Montague, Grégoire Altan-Bonnet, Armita Nourmohammad.
      Cytotoxic T lymphocytes eliminate infected or malignant cells, safeguarding surrounding tissues. Although experimental and systems-immunology studies have cataloged many molecular and cellular actors involved in an immune response, the design principles governing how the speed and magnitude of T cell responses emerge from cellular decision-making remain elusive. Here, we recast the T cell response as a feedback-controlled program, wherein the rates of activation, proliferation, differentiation, and death are regulated through antigenic, pro- and anti-inflammatory cues. By exploring a broad class of feedback-controller designs as potential immune programs, we demonstrate how the speed and magnitude of T cell responses emerge from optimizing signal-feedback to protect against diverse infection settings. We recover an inherent trade-off: infection clearance at the cost of immunopathology. We show how this trade-off is encoded into the logic of T cell responses by hierarchical sensitivity to different immune signals. Notably, we find the designs that balance harm from acute infections and autoimmunity produce immune responses consistent with the experimentally observed patterns of T cell effector expansion in mice. Extending our model to immune-based T cell therapies for cancer tumors, we quantify the trade-off between the affinity for tumor antigens ("quality") and the abundance ("quantity") of infused T cells necessary for effective treatment. Finally, we show how therapeutic efficacy can be improved by targeted genetic perturbations to T cells. Our findings offer a unified control-logic for cytotoxic T cell responses and point to specific regulatory programs that can be engineered for more robust T cell therapies.
    Keywords:  Pareto optimality; T cells; cell-fate decision-making; feedback control
    DOI:  https://doi.org/10.1073/pnas.2528202123
  28. J Med Invest. 2026 ;73(1.2): 212-216
    Soy isoflavone, Soyaflavone HG, improves low T cell proliferation response in aged BALB/c mice.
    Moeka Tomonobu, Karen Mori, Akiko Nakamoto, Mariko Nakamato, Tohru Sakai.
      Aging is a phenomenon in which cells, tissues and organs undergo systemic pathological changes. We examined the effects of soy isoflavone on immune function in aged mice. Although aged mice showed lower T cell response against anti-CD3 monoclonal antibody stimulation than did young mice, aged mice have treated with soy isoflavone reversed the low responses. The percentage of CD4+ cells was higher in aged mouse splenocytes treated with soy isoflavone than in untreated mouse splenocytes. Unexpectantly, aged mice treated with soy isoflavone showed higher programmed cell death-1 expression on T cells than did aged control mice. These results showed that soy isoflavone improve low T cell proliferation response in aged mice. J. Med. Invest. 73 : 212-216, February, 2026.
    Keywords:  PD-1; Soyaflavone HG; T cell function; aging; soy isoflavone
    DOI:  https://doi.org/10.2152/jmi.73.212
  29. JCI Insight. 2026 Apr 23. pii: e193752. [Epub ahead of print]
    Co-administration of Rapamycin with a DNA/MVA SIV Vaccine Improves Memory CD8 T Cell Response.
    Shanmugalakshmi Sadagopal, Kasey Stokdyk, Suefen Kwa, Rahul Basu, Sailaja Gangadhara, Rafi Ahmed, Smita S Iyer, Koichi Araki, Rama Rao Amara.
      Inhibiting the mammalian target of rapamycin (mTOR) during acute viral infection generates highly functional memory CD8 T cells. We investigated the effects of inhibiting mTOR by using rapamycin during the effector and contraction phases of the immune response to a DNA prime and Modified Vaccinia Ankara (MVA) boost SIV vaccination in rhesus macaques. Rapamycin administered either during MVA boosts alone (DMR) or during both primes and boosts (DRMR) reduced the contraction of effector CD8 T cells, resulting in higher frequencies of SIV-specific memory CD8 T cells with enhanced quality as indicated by expression of Bcl-2 and CD127. Additionally, rapamycin reduced the frequency of proliferating CCR5+ CD4 T cells in the blood following the MVA boost. Post SIV251 infection, rapamycin-treated macaques demonstrated marked expansion of SIV-specific CD8 T cells (reaching up to 50% in blood and 25% in gut). The heightened expansion of SIV-specific CD8 T cells in the DMR group was associated with markedly lower (2-logs compared to unvaccinated and 1-log compared to DM) peak viral load in the gut and set-point viremia, along with improved survival post infection. Thus, inhibiting the mTOR pathway during MVA boosts of a DNA/MVA vaccine enhances vaccine efficacy by improving memory CD4 and CD8 T cell function.
    Keywords:  AIDS vaccine; AIDS/HIV; Cellular immune response; Immunology; Infectious disease
    DOI:  https://doi.org/10.1172/jci.insight.193752
  30. Nanoscale. 2026 Apr 22.
    Nanoparticle-mediated metabolic reprogramming for immune modulation in inflammatory diseases.
    Hailing Wang, Ahequeli Gemingnuer, Yan Liu, Yinan Wang, Xin Meng.
      Dysregulated immune cell metabolism including abnormal glycolysis, mitochondrial dysfunction, and excessive reactive oxygen species (ROS) generation contributes to the pathogenesis of various inflammatory diseases. Recent advances in immunometabolism have highlighted the critical role of metabolic reprogramming in shaping immune responses during chronic inflammation. However, a lack of selectivity for specific immune cells or tissues often leads to off-target effects. Nanoparticle-based therapeutic strategies have emerged as a promising platform for modulating immune cell metabolism with improved precision, enhanced bioavailability, and reduced systemic toxicity. Despite progress in this field, there has been no comprehensive review in recent years that systematically summarizes the use of engineered nanocarriers for immunometabolic regulation in inflammatory diseases. This review provides a systematic overview of nanoparticle-mediated metabolic reprogramming for the treatment of inflammatory diseases. These nanoparticles not only serve as delivery vehicles for metabolic modulators but also actively participate in immune regulation through their physicochemical properties and surface functionalities. Furthermore, this review analyzes early-stage clinical studies and the patent landscape, indicating encouraging efficacy and safety profiles for nanoparticle-based metabolic therapies. Collectively, nanoparticle-mediated immunometabolic reprogramming offers a transformative approach for precision intervention in inflammatory diseases.
    DOI:  https://doi.org/10.1039/d5nr04062k
  31. J Transl Med. 2026 Apr 24.
    Mitochondria at the heart of aging: structure, function, and failure.
    Hany E Marei.
      
    Keywords:  Aging; Mitochondria; Mitochondrial biogenesis; Mitochondrial dysfunction; Mitophagy; NAD+; Oxidative stress; PGC-1α; Rejuvenation; Sirtuins
    DOI:  https://doi.org/10.1186/s12967-026-08047-8
  32. Sci Transl Med. 2026 Apr 22. 18(846): eaed0042
    Expansion of stemlike HIV-specific CD8+ T cells and limited viral epitope diversity characterize durable posttreatment control of HIV.
    Charles R Crain, Aljawharah Alrubayyi, Itai Muzhingi, Anna Traunbauer, Esther Jeon, Rinki Deo, Efthimios A Deligiannidis, Prerana Shrestha, Behzad Etemad, Hannah MacLeod, Gregory M Laird, Manish C Choudhary, Michael J Peluso, Steve G Deeks, Rachel L Rutishauser, Jonathan Z Li, Gaurav D Gaiha.
      Individuals who durably control HIV after cessation of antiretroviral therapy (ART) are of great interest for HIV cure efforts, but the correlates of posttreatment control remain incompletely understood. Here, we show across a diverse cohort of posttreatment controllers (PTCs), posttreatment noncontrollers (NCs), and spontaneous elite controllers (ECs) that robust expansion of HIV-specific CD8+ T cells and reduced viral reservoir diversity were strongly associated with durable (>1 year) viral suppression after ART cessation. In addition, HIV-specific CD8+ T cells in PTCs exhibited a stemlike memory phenotype, characterized by high TCF-1 (T cell factor 1) and low TOX (thymocyte selection-associated HMG box) expression, and readily differentiated into cytolytic effectors. Mapping of CD8+ T cell responses from PTCs revealed broad targeting of epitopes in a conserved autologous reservoir, whereas preferential targeting of epitopes derived from mutationally constrained regions was primarily a feature of CD8+ T cells from ECs. Univariable and additive analyses revealed a link between HIV-specific CD8+ T cell expansion, a stemlike phenotype, and conservation of human leukocyte antigen class I-restricted viral epitopes with posttreatment control. Together, these findings identify features of HIV-specific CD8+ T cells and the viral reservoir that are associated with sustained HIV control after ART cessation, informing future immunotherapeutic strategies toward achieving an HIV cure.
    DOI:  https://doi.org/10.1126/scitranslmed.aed0042
  33. NPJ Biomed Innov. 2026 Jan 16. pii: 5. [Epub ahead of print]3(1):
    Mechanical regulation of metabolism, epigenetics, and their interplay.
    Hoonsik Nam, Gyusang Yu, Seor I Ahn, Sungmin Nam.
      Mechanical cues from the cellular microenvironment critically influence cell behavior, fate, and function through coordinated regulation of metabolism and gene expression. This review discusses how mechanical signals are sensed and transduced into biochemical responses that reshape metabolic pathways and the epigenetic landscape. We highlight emerging evidence linking mechanotransduction, metabolic reprogramming, and chromatin modifications, and propose directions for future research to unravel how mechanical forces orchestrate this dynamic and reciprocal interplay.
    DOI:  https://doi.org/10.1038/s44385-025-00059-1
  34. Reprod Sci. 2026 Apr 22.
    CD8+ T Cells in Association with SCD1 Regulate Cervical Cancer and Tumour Microenvironment Correlation Research.
    Qi Bao, Zihan Wang, Guanghua Gu, Wei Wang, Shuangyang Qin, Shihui Zhang, Weipei Zhu.
      
    Keywords:  CD8+ T; Cervical cancer; Ferroptosis; ROS; SCD1
    DOI:  https://doi.org/10.1007/s43032-026-02070-2
  35. Elife. 2026 Apr 22. pii: RP105821. [Epub ahead of print]14
    Clathrin-independent endocytosis and retrograde transport in cancer cells tune immune synapse organization and CD8 T cell response.
    Shiqiang Xu, Alix Buridant, Thibault Hirsch, Céline Duhamel, Benjamin Ledoux, Massiullah Shafaq-Zadah, Estelle Dransart, Louise Thines, Ludger Johannes, Pierre Van der Bruggen, Pierre Morsomme, Henri-François Renard.
      Endophilin A3-mediated clathrin-independent endocytosis (EndoA3-mediated CIE) contributes to the internalization of immunoglobulin-like proteins, including key immune synapse components. Here, we identify ICAM1 as a novel EndoA3-dependent cargo, alongside ALCAM. We demonstrate that both proteins subsequently follow retromer-dependent retrograde transport to the trans-Golgi network (TGN) in cancer cells. From there, we propose that they undergo polarized redistribution to the plasma membrane, where they contribute to immune synapse formation between cancer cells and cytotoxic CD8 T cells. Disruption of EndoA3 or retromer components significantly affects the response of autologous cytotoxic CD8 T cells, as evidenced by reduced cytokine production and secretion, but increased lytic activity, while proliferation and later activation marker expression remain intact. This is accompanied by diminished ICAM1 density at the immune synapse, where we observe it arriving via polarized vesicular transport, indicating altered synapse organization. Indeed, cancer cells lacking EndoA3-mediated CIE or retromer form enlarged immune synapses that fail to sustain full T cell cytokine secretion, suggesting a compensatory attempt by T cells to overcome the defective synapse, while likely promoting more transient contacts that potentially favor serial killing. Together, these findings reveal that EndoA3-mediated CIE and retrograde transport act in concert in cancer cells to relocate immune synapse components via the Golgi, thereby fine-tuning the balance between cytotoxic T cell cytokine secretion and lytic activity. These insights contribute to a better understanding of the mechanisms governing immune synapse formation and organization, providing a necessary foundation for the long-term identification of new strategies to enhance T cell-mediated anti-tumor immunity.
    Keywords:  CD8 T cell; cancer cell; cell biology; endocytosis; human; immune synapse; immunoglobulin; immunology; inflammation; retrograde transport
    DOI:  https://doi.org/10.7554/eLife.105821
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒26 at 6:08.