bims-imseme 2026-04-19 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–04–19
25 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

ATF7ip inhibits the tumor immune response by promoting terminal CD8+ T cell Exhaustion.
Extracellular ATP Functions as a Metabolic Lineage Selection Signal That Stabilizes Tc9 Cells During Adoptive T Cell Therapy.
Diet-induced metabolic memory shapes CD8+ T cell ferroptosis susceptibility.
Stem-like PD-1+TCF-1+ CD8+ T cells result from helpless priming and rely on CD4+ T-cell help to complete their cytotoxic effector differentiation.
AI-guided discovery of the IRF4-PAICS-LDHA axis as a multitarget hub linking tumor metabolism to CD8+ T cell exhaustion in DLBCL.
Immunometabolic reprogramming in sepsis: mechanisms, clinical endotypes, and therapeutic opportunities.
CD8+ T cells contribute to arterial aging in mice.
Purine salvage pathway protects CD8+ T cells from metabolic stress.
Distinct dendritic cell cytoskeletal programs dictate synapse architecture and CD8+ T cell fate.
Viral vector-free generation of orthogonal IL-2-responsive CAR T cells through gene editing of IL-2 and its receptor.
BATF3 regulates differentiation of CD8+ T lymphocytes and memory differentiation program.
Single-day nonactivated IL-18-armed CAR T cells establish a durable, stemlike state with enhanced persistence.
T cell exhaustion in Giardia intestinalis infection: A review.
On-demand GLUT3 expression augments CAR T cell metabolic fitness and antitumor efficacy in preclinical models of glioblastoma.
T cells in antibody-associated CNS autoimmunity: a mechanistic approach across autoimmune encephalitis and paraneoplastic disorders.
The dual role of TOX in regulating TH1 and CD8+ T cell fate.
Metabolic oxidoreductases: central regulators of the epigenetic landscapes in stemness.
Identity, ontogeny, and age-related changes in splenic white pulp macrophages in mouse and human spleen.
Dual-Engineered Dendritic Cell Derived Small Extracellular Vesicles Couple T Cell Priming with Checkpoint Reprogramming for Synergistic Immunotherapy.
Mitochondrial dysfunction in immune cells during the perioperative period: mechanisms, emerging therapeutic strategies, and implications for multi-organ protection.
Fatty acid metabolism-an emerging regulatory node in T-cell immunometabolism.
Human Lymph Node Cellular Senescence Atlas Reveals Age-Dependent Alteration in Germinal Center B Cell Function and Niches.
Aging restricts maturation of CXCL13 + T follicular helper cells in human immunity.
Peripheral CD8⁺ T cell subsets and physical frailty in community-dwelling older Thai adults: the role of age and multimorbidity.
Dietary Interventions for Healthy Aging: An Epigenetic Perspective.

Cancer Immunol Res. 2026 Apr 13.

ATF7ip inhibits the tumor immune response by promoting terminal CD8+ T cell Exhaustion.

Sujit Kashyap, Jun Hyung Sin, Sophia M Guldberg, Jacqueline L Yee, Maya Lopez-Ichikawa, Sloan H Phillips, Matthew H Spitzer, Michael Waterfield.

CD8+ T cell exhaustion limits the immune response to tumors because of ineffective T cell effector functions. Thus, therapies that inhibit T-cell exhaustion are critical for optimizing cancer treatment. Recent studies have implicated epigenetic proteins in T-cell exhaustion. Here, we identified activating transcription factor 7 interacting protein (ATF7ip) as an epigenetic protein critical for inducing T cell exhaustion. Loss of Atf7ip in CD8+ T cells resulted in decreased terminal exhaustion and increased numbers of progenitor-exhausted cells in both chronic viral infections and cancer. Given the decreased T cell terminal exhaustion observed with Atf7ip-deficiency in CD8+ T cells, this may be one mechanism that leads to decreased tumor burden. Mechanistically, ATF7ip functions to stimulate the deposition of repressive H3K9me3 at critical immune-effector gene loci, such as Il7r and Il2 leading to enhanced exhaustion. Our data suggest that ATF7ip may be a rational target for deletion in adoptive T-cell therapies to reduce CD8+ T-cell exhaustion.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0816
Int J Mol Sci. 2026 Mar 31. pii: 3169. [Epub ahead of print]27(7):

Extracellular ATP Functions as a Metabolic Lineage Selection Signal That Stabilizes Tc9 Cells During Adoptive T Cell Therapy.

Jie Ren, Zhengrong Gong, Yutong Zhong, Ruipei Xiao, Khadija Urooj, Yuan Gao, Enguang Bi, Handuo Wang.

  Adoptive T cell therapy (ACT) remains limited in solid tumors by poor T cell persistence within the metabolically hostile tumor microenvironment (TME). Although IL-9-producing CD8+ T cells (Tc9) consistently demonstrate superior antitumor efficacy compared with conventional Tc1 cells, the selective pressures that shape their functional advantage remain unclear. Here, we show that effective ACT-mediated tumor control is accompanied by a marked increase in intratumoral extracellular ATP (eATP), representing a common metabolic consequence of tumor cell destruction. Despite comparable ATP accumulation following Tc1 or Tc9 treatment, these subsets exhibit strikingly distinct responses to ATP stress. Tc1 cells are highly susceptible to ATP-induced apoptosis, whereas Tc9 cells display intrinsic resistance, resulting in superior in vivo persistence. Mechanistically, Tc9 cells actively convert ATP signaling into enhanced mitochondrial fitness, characterized by increased oxidative phosphorylation and spare respiratory capacity. ATP exposure further drives Tc9 cells toward a tissue-resident memory (TRM) phenotype through activation of the TGF-β signaling axis. Transcriptomic and molecular analyses reveal that purinergic signaling pathways, including elevated expression of the ATP receptor P2RX7, are intrinsically enriched in Tc9 cells and are further amplified upon ATP stimulation. Collectively, our findings identify extracellular ATP as a metabolic lineage selection signal in ACT, demonstrating that ATP stress preferentially stabilizes metabolically resilient Tc9 cells by linking purinergic sensing to mitochondrial remodeling and TRM programming, thereby providing a conceptual basis for enhancing the persistence and efficacy of engineered T cell therapies in solid tumors.

Keywords:  ATP; IL-9+ CD8+ T cells; adoptive T cell therapy (ACT); cancer immunotherapy; mitochondria; resident memory T cells (TRM)

DOI:  https://doi.org/10.3390/ijms27073169
Nat Immunol. 2026 Apr 13.

Diet-induced metabolic memory shapes CD8+ T cell ferroptosis susceptibility.

Ryan P Mansell, Whitney S Henry.

DOI: https://doi.org/10.1038/s41590-026-02493-8
J Immunother Cancer. 2026 Apr 12. pii: e014041. [Epub ahead of print]14(4):

Stem-like PD-1+TCF-1+ CD8+ T cells result from helpless priming and rely on CD4+ T-cell help to complete their cytotoxic effector differentiation.

Julia Busselaar, Douwe M T Bosma, Mo D Staal, Xin Lei, Yanling Xiao, Jannie Borst.

   BACKGROUND: Antigen-specific CD8+ T cells can be in a stem-like programmed cell death protein-1 (PD-1)+TCF-1+ differentiation state that progresses into terminal exhaustion in cancer and chronic infection. These stem-like cells are important, since they are the responders to PD-1 targeted immunotherapy and a potential resource for antitumor immunity.
METHODS: We use a mouse vaccination model to delineate by spectral flow cytometry and single-cell RNA sequencing the effects of CD4+ T-cell help during priming on the differentiation fate of stem-like CD8+ T cells. We use bioinformatic analysis to extrapolate our data to mouse models of cancer and chronic infection. We next explore CD8+ T-cell differentiation states and delivery of CD4+ T-cell help in the immunogenic MC38 tumor model.
RESULTS: Upon vaccination in the absence of help signals, stem-like CD8+ T cells do not further differentiate and accumulate in the draining lymph node. When help signals are delivered, stem-like CD8+ T cells proliferate and differentiate into circulating cytotoxic effector cells. Stem-like CD8+ T cells raised by vaccination in presence or absence of CD4+ T-cell help have an identical transcriptome, which they share with stem-like CD8+ T cells defined in mouse models of cancer and chronic infection. The immunogenic MC38 tumor harbors endogenous helper epitopes, but primes stem-like CD8+ T cells rather than helped cytotoxic effectors. Therapeutic vaccination with endogenous helper epitopes does not improve MC38 tumor control. Intratumoral expression of strong, exogenous helper epitopes as present in our vaccine improves tumor control, but does not efficiently convert stem-like tumor-specific CD8+ T cells into helped cytotoxic effectors.
CONCLUSIONS: Our data argue that stem-like CD8+ T cells are helpless cells that lie at the bifurcation point of CD8+ T-cell effector and exhaustion trajectories. Even though the immunogenic MC38 tumor expresses helper epitopes, it primarily raises stem-like CD8+ T cells, indicating that help delivery is impaired in this tumor context. Promoting the efficient delivery of help signals to stem-like tumor-specific CD8+ T cells to drive their expansion and differentiation into cytotoxic effectors is therefore an important therapeutic challenge in cancer and other conditions that lead to T-cell exhaustion.

Keywords:  Immunotherapy; T cell; Tumor infiltrating lymphocyte - TIL; Vaccine; co-inhibitory molecule

DOI:  https://doi.org/10.1136/jitc-2025-014041
NPJ Precis Oncol. 2026 Apr 16.

AI-guided discovery of the IRF4-PAICS-LDHA axis as a multitarget hub linking tumor metabolism to CD8+ T cell exhaustion in DLBCL.

Zeyuan Wang, Liye Wang, Siyu Qian, Yue Zhang, Qing Yang, Zhenzhen Yang, Shaoxuan Wu, Meng Dong, Zhiqi Zhang, Xufeng Wei, Minglei Yang, Hui Meng, Enjie Liu, Guozhong Jiang, Xudong Zhang, Wencai Li, Qingjiang Chen.

Diffuse large B-cell lymphoma (DLBCL) features an immunosuppressive tumor microenvironment (TME), yet the molecular drivers connecting metabolic reprogramming to immune evasion remain poorly defined. Here, we deployed an integrative single-cell transcriptomic analysis combined with a machine learning (ML) framework to systematically identify key immune-suppressive hubs in DLBCL. Through ML-driven prioritization of a 33-gene panel, PAICS emerged as a central node within an immunosuppressive B-cell subgroup. Functional assays confirmed that PAICS promotes lymphoma proliferation, survival, and tumor growth while establishing an immunosuppressive TME-marked by reduced IFN‑γ, elevated TGF‑β and IL‑10, and enhanced CD8⁺ T cell exhaustion. Mechanistically, we uncovered the IRF4-PAICS-LDHA axis: IRF4 transcriptionally activates PAICS, which physically interacts with LDHA to augment its activity, thereby skewing the NAD⁺/NADH balance toward metabolic immunosuppression. Importantly, our AI-aided approach not only identified this axis but also predicted its vulnerability to metabolic intervention: both methotrexate treatment and LDHA knockdown restored metabolic balance, reversed T‑cell exhaustion, and suppressed tumor growth. These findings highlight the power of ML in uncovering multi-targetable metabolic-immune networks and in guiding therapeutic strategies to overcome immune evasion in DLBCL.

DOI: https://doi.org/10.1038/s41698-026-01428-8
Front Immunol. 2026 ;17 1731995

Immunometabolic reprogramming in sepsis: mechanisms, clinical endotypes, and therapeutic opportunities.

Chibo Liu, Yanqun Cai, Qinfei Ma, Wei Sun.

  Sepsis, a systemic inflammatory syndrome triggered by infection, is tightly linked to dysregulated host immunometabolism. We review three hallmark metabolic alterations. First, a shift from oxidative phosphorylation (OXPHOS) to glycolysis provides rapid ATP early on; prolonged glycolytic engagement, however, drives excessive cytokine release through abnormal accumulation of metabolic intermediates. Second, impaired fatty acid oxidation (FAO) and disrupted cholesterol homeostasis not only compromise energy supply but also amplify pro-inflammatory signaling. Third, mitochondrial dysfunction unleashes reactive oxygen species (ROS) and derails metabolic homeostasis, promoting multi-organ injury. Notably, short-chain fatty acids (SCFAs) derived from the gut microbiota fine tune pro-versus anti-inflammatory responses via epigenetic regulation of immune cells. We further discuss how metabolic reprogramming governs macrophage polarization and T cell exhaustion, and we summarize therapeutic strategies that target key metabolic nodes. This review provides an integrated perspective on the immunometabolic mechanisms of sepsis and offers a rationale for metabolism-based precision interventions.

Keywords:  T cells; macrophages; metabolic reprogramming; sepsis; short-chain fatty acids

DOI:  https://doi.org/10.3389/fimmu.2026.1731995
J Immunol. 2026 Apr 15. pii: vkag060. [Epub ahead of print]215(4):

CD8+ T cells contribute to arterial aging in mice.

David J Buckley, Sogol Zahedi, Alexandra Canizales, Nathan E Cuellar, Kidist Bogale, Katherine A Smith, Konner J Terrebonne, Sunita Sharma, Blessy Joseph, Jody L Greaney, Daniel W Trott.

  We have previously reported that T cells accumulate in the arteries of old mice and mechanistically contribute to the development of age-related arterial dysfunction. However, the specific T cell subtype that is the primary contributor to arterial aging is unknown. There is substantial evidence that CD8+ T cells are more susceptible to the effects of aging compared with their CD4+ counterparts. We hypothesized that CD8+ T cell-specific depletion would ameliorate large-artery stiffness and augment endothelium-dependent dilation in old mice but not in young mice. We observed that old mice exhibited a greater accumulation of CD8+, but not CD4+, T cells in the aorta and mesentery compared with their young counterparts. Further, pharmacological depletion of CD8+, but not CD4+, T cells resulted in lower aortic stiffness and blunted aortic collagen. In addition, old CD8+, but not CD4+, depleted mice demonstrated augmented endothelium-dependent dilation via greater nitric oxide bioavailability. These data indicate that CD8+ T cells are the specific T cell subtype that contributes to age-related arterial dysfunction.

Keywords:  adaptive immunity; aortic stiffness; nitric oxide bioavailability

DOI:  https://doi.org/10.1093/jimmun/vkag060
Nat Immunol. 2026 Apr 13.

Purine salvage pathway protects CD8+ T cells from metabolic stress.

Masaki Tajima, He Hao, Baihao Zhang, Yuta Matsuoka, Kazuhiro Sonomura, Koshi Imami, Yosuke Isobe, Rae Maeda, Yu-Hsien Lin, Akihiro Shimba, Ryoma Kato, Pedro Henrique Costa Cruz, Sayaka Washizu, Yosuke Ikejiri, Akiyo Morinibu, Clive Steven Barker, Jun Seita, Yibo Wu, Satomi Ito, Seiko Narushima, Rei Nakano, Mikako Maruya, Wakana Kobayashi, Sai Shanmukha Priya Narayanan, Jumana Shaheen, Hiroyuki Neyama, Ken-Ichi Yamada, Makoto Arita, Yuki Sugiura, Sidonia Fagarasan.

Metabolic stress from a high-fat diet (HFD) impairs antitumor immunity through persistent metabolic rewiring, but its effects and long-term impact on CD8+ T cell metabolism remain unknown. Here, we found that even temporary exposure to a HFD impaired antitumor immunity 10 weeks after reversion to a normal diet. This was due to lasting metabolome changes that included enrichment in phospholipids sensitive to peroxidation and depletion of antioxidants, affecting the survival and function of CD8+ T cells. Under oxidative stress, CD8+ T cells utilized the xanthine salvage pathway to produce guanosine triphosphate, enhancing the amount of tetrahydrobiopterin. Xanthine supplementation reduced lipid peroxidation in tumor-draining lymph nodes and improved antitumor immunity in mice previously on a HFD. Our data indicate that metabolic stress in CD8+ T cells persists long after restoration of a balanced diet, and manifests as vulnerability to ferroptosis, which could be mitigated by replenishing biopterins through the xanthine salvage pathway.

DOI: https://doi.org/10.1038/s41590-026-02491-w
Front Immunol. 2026 ;17 1716644

Distinct dendritic cell cytoskeletal programs dictate synapse architecture and CD8+ T cell fate.

Camille D Clamagirand, Christoph Ratswohl, Marc W Schmid, Theresia Eich, Nadine Anslinger, Daniel F Legler, Jérémie Rossy.

  Dendritic cell activation of CD8+ T cells at the immunological synapse is critical for immunity, but the structural organization of the dendritic cell side and its impact on T cell fate remain poorly defined. Using bone marrow-derived dendritic cells (BMDCs) as a model, we describe two stable subpopulations distinguished by their capacity to form morphologically distinct synapses. We demonstrate that this architectural divergence is governed by the differential expression of the co-stimulatory molecule CD70: CD70high BMDCs form spiky "firework" synapses driven by a filopodia-based cytoskeletal program, while CD70low BMDCs form smooth "pancake" synapses. This structural dichotomy functionally dictates T cell programming. CD70high dendritic cells prime potent, terminally differentiated Tc1 effector cells. In contrast, IL-6-secreting CD70low dendritic cells generate memory T cells with a Tc17-like functional profile and robust recall capacity. Our work reveals that DC synapse architecture is a key determinant of T cell fate, linking the physical organization of the cell to distinct immunological outcomes.

Keywords:  CD70; T cell; T cell-DC interactions; actin cytoskeleton; dendritic cell; immunological synapse

DOI:  https://doi.org/10.3389/fimmu.2026.1716644
Blood Immunol Cell Ther. 2025 Dec;pii: 100019. [Epub ahead of print]1(3):

Viral vector-free generation of orthogonal IL-2-responsive CAR T cells through gene editing of IL-2 and its receptor.

Qian Zhang, Yihao Wu, Jingyi Yang, Kevin Zhou, Eric Nigel Ebenezer Anand Manoharan, Tyra Wentz, Leon Su, Alvin Yu, Hong-Yi Wang, Laurakay Bruhn, Israel Steinfeld, Nicolas Gonzalez, Edward Z Song, Yunlin Zhang, Morgan E Hresko, Daniel E Ryan, Nils W Engel, Selene Nunez-Cruz, Carl H June, K Christopher Garcia, Michael C Milone.

Building on the enhancing effects of the orthogonal interleukin-2 (oIL-2) system for T-cell immunotherapy, we explored a viral vector-free strategy for generating orthogonal chimeric antigen receptor (orthoCAR) T cells. We show that prime editing can generate orthogonal IL-2Rβ (oIL-2Rβ) mutations in T cells with an average efficiency of 72% (range, 54%-89%). The mutations are functional, enrich ex vivo when cultured with oIL-2 and enhance the engraftment, efficacy, and toxicity of CAR T cells in vivo comparable to orthoCAR T cells generated by cotransduction of the oIL-2Rβ and CAR. We further show that the insertion of a CD19-specific CAR with a chicken β-globin promoter into the IL-2 locus (IL-2-CAR19) can be achieved by a CRISPR/CRISPR-associated protein 9 (Cas9)-triggered homology-directed repair with an average efficiency of 46% (range, 30%-65%) in primary T cells. IL-2-CAR19 T cells show a >3-log reduction in IL-2 production consistent with a >96% IL-2 gene disruption. Despite the loss of autocrine IL-2 secretion, IL-2-CAR19 T cells rapidly and potently kill NALM-6 leukemic cells in vitro and in vivo without the need for exogenous IL-2 support. Combining the prime editing of oIL-2Rβ with IL-2-CAR19 T cells yields orthoCAR T cells that exhibit in vitro and in vivo function comparable to lentivirally generated orthoCAR T cells. The prime editing of oIL-2Rβ expands the potential application of the orthogonal IL-2 system to existing T-cell therapies. Moreover, the robust functional activity of IL-2-CAR19 cells highlights the dispensable nature of the IL-2 gene in CAR T cells and its availability for the target insertion of genetic payloads.

DOI: https://doi.org/10.1016/j.bict.2025.100019
Life Sci Alliance. 2026 Jul;pii: e202503550. [Epub ahead of print]9(7):

BATF3 regulates differentiation of CD8+ T lymphocytes and memory differentiation program.

Koji Umemura, Yasuhiro Kojima, Jakrawadee Julamanee, Yusuke Okuno, Yuki Takeuchi, Fumiya Ohara, Shihomi Kuwano, Yoshitaka Adachi, Ryo Hanajiri, Seitaro Terakura, Hitoshi Kiyoi.

CD8+ T lymphocytes differentiate from effector to memory cells after antigen clearance, with prolonged IL-2 production characterizing functional cytotoxic T lymphocytes (CTLs). To identify transcription factors associated with sustained IL-2 production, we compared influenza virus-specific and cytomegalovirus-specific CTLs, identifying Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF3) as a key candidate. BATF3 overexpression significantly enhanced cell proliferation in both virus-specific CTLs and CD19 chimeric antigen receptor T (CAR-T) cells while reducing cytokine production. Among AP-1 transcription factor family members, BATF and BATF3 demonstrated similar functions during effector phase expansion, but BATF3 exhibited distinct roles in promoting memory cell formation. ATAC-seq analysis revealed that BATF3 overexpression dynamically regulates chromatin accessibility, affecting diverse cellular processes including cytoskeletal organization, metabolic pathways, and survival signaling. BATF and BATF3 showed comparable kinetics until peak expansion, but BATF3 specifically facilitated the transition from effector to memory phase, up-regulating memory-associated genes while down-regulating exhaustion markers. These findings establish BATF3 as a master regulator of CD8+ T-cell fate determination through chromatin remodeling, offering therapeutic targets for enhancing CAR-T cell persistence in immunotherapy.

DOI: https://doi.org/10.26508/lsa.202503550
Blood. 2026 Apr 16. pii: blood.2026033460. [Epub ahead of print]

Single-day nonactivated IL-18-armed CAR T cells establish a durable, stemlike state with enhanced persistence.

Joseph S Durgin, Shin H Seo, Shadab Kazmi, Bakir Valentić, Chloe Leff, Martina Markovska, Xiaoling Jin, Feng Shen, Abdulla Berjis, Nandana Mukherjee, Ashwin Sannecy, Gabriela Plesa, Khatuna Gabunia, John Scholler, Saar I Gill, Roddy S O'Connor, Carl H June, Saba Ghassemi.

Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment of B-cell malignancies, yet challenges including manufacturing delays, T-cell exhaustion, and limited persistence impede broader clinical success. Here, we report the single day production of non-activated CAR T-cells engineered to secrete interleukin-18 (IL-18), a pro-inflammatory cytokine that enhances T-cell function. These non-activated CART-IL18 cells exhibit robust anti-tumor efficacy across xenograft models of lymphoma, leukemia, and pancreatic cancer. IL-18 expression enhances the functional advantages of naïve-like non-activated CAR T-cells, resulting in improved persistence, metabolic fitness, and resistance to exhaustion. Single-cell transcriptomic analysis revealed upregulation of IL7R, KLF2, and MCL1, alongside suppression of inhibitory checkpoint genes such as PDCD1, TOX, and HAVCR2. Metabolomic profiling demonstrated enhanced mitochondrial bioenergetics, with increased spare respiratory capacity and accumulation of α-ketoglutarate, malate, and spermine. Functional in vitro and in vivo profiling demonstrated enhanced per-cell cytotoxicity and in vivo durability. We complemented these studies with single-cell transcriptomic and metabolomic analyses to define CAR T-cell biological states beyond what is captured by xenograft tumor clearance. This IL-18-enhanced, activation-free CAR T product offers a clinically actionable platform with the potential to reduce vein-to-vein time while improving product potency and persistence, providing a rationale for clinical testing in patients with tumors refractory to standard CAR T.

DOI: https://doi.org/10.1182/blood.2026033460
Parasite Epidemiol Control. 2026 May;33 e00500

T cell exhaustion in Giardia intestinalis infection: A review.

Williams Walana, Frank Yelevuuro Dasaa, Jennifer Suurbaar.

   Background: Giardiasis, caused by the protozoan parasite Giardia intestinalis, is a gastrointestinal infection responsible for approximately 280 million cases of gastroenteritis worldwide each year. While T cells are crucial in the host's defence against G. intestinalis, it is unclear which T cell subsets actively help control the infection.
Objective: This review aims to synthesise existing literature on the relationship between T cell exhaustion and giardiasis, examine the T cell subsets affected, identify diagnostic markers that reflect the severity of Giardia infection, and explore potential vaccine development.
Methodology: A comprehensive database search from Google Scholar and Medline/PubMed identified eligible studies that reported on T cell exhaustion markers, immune response and giardiasis. Search terms included "Giardia", "Giardiasis", "T cells" and "T cell exhaustion". Articles were reviewed for data on T-cell function, cytokine expression, and immune responses in people with giardiasis.
Results: T cell exhaustion is common in giardiasis, as indicated by the findings. There are higher proliferation rates and upregulation of surface activation markers in CD4 cells in Giardia infection. Natural regulatory T cell levels (CD4+, CD25+, and Foxp3+) are significantly increased in Giardia infection. Chronic giardiasis and co-morbidity contribute to T-cell exhaustion.
Conclusion: The activation and proliferation of T cells are key to the clearance of Giardia infection. Most cytokine profiles are markedly elevated during Giardia infection. Cytokine responses vary depending on host immunity and parasite load. Understanding the roles of cytokines in both T-cell and B-cell-mediated immunity could guide treatment protocols and control measures.

Keywords:  G. Duodenalis; Giardia intestinalis; Giardia lamblia; Giardiasis; Immune exhaustion; T cell exhaustion

DOI:  https://doi.org/10.1016/j.parepi.2026.e00500
Sci Transl Med. 2026 Apr 15. 18(845): eadu3532

On-demand GLUT3 expression augments CAR T cell metabolic fitness and antitumor efficacy in preclinical models of glioblastoma.

Junya Yamaguchi, Keisuke Watanabe, Akihiro Nakamura, Nina Yi-Tzu Lin, Sachi Maeda, Daisuke Sugiyama, Shinichiro Kato, Akihito Nagata, Hitomi Nishinakamura, Kota Itahashi, Shohei Koyama, Hiroyuki Mizoguchi, Yukihiro Shiraki, Atsushi Enomoto, Fumiharu Ohka, Kazuya Motomura, Yuichiro Tsukada, Masaaki Ito, Yuka Maeda, Ryuzo Ueda, Atsushi Natsume, Ryuta Saito, Hiroyoshi Nishikawa.

The clinical success of chimeric antigen receptor T cell (CAR T cell) therapy in hematologic malignancies has prompted its application for refractory solid tumors, including glioblastoma (GBM). However, CAR T cell trials against solid tumors have failed to show clinical efficacy thus far. Here, we show that the dysfunction of CAR T cells in GBM is attributed, at least, in part, to glucose deficiency in the tumor microenvironment (TME) driven by the substantial consumption of glucose by cancer cells. Engineering CAR T cells to continuously express glucose transporter 3 (GLUT3), a high-affinity glucose transporter, restored their cytokine production and killing activity. However, although CAR T cells with stable GLUT3 expression induced tumor reduction in a preclinical GBM model, their overactivation led to adverse events and mouse death. In contrast, on-demand GLUT3-expressing CAR T cells, in which GLUT3 transcription was driven by the nuclear translocation of nuclear factor of activated T cells (NFAT) as a consequence of target antigen stimulation, exhibited enhanced metabolic fitness and increased antitumor efficacy, leading to long-lasting tumor control in intracranial human GBM cell xenograft models while preventing adverse events. We propose that on-demand enhancement of metabolic fitness, such as at the time of exposure to tumor antigens, is a concept for boosting the antitumor efficacy of CAR T cells against solid tumors.

DOI: https://doi.org/10.1126/scitranslmed.adu3532
Curr Opin Neurol. 2026 Apr 15.

T cells in antibody-associated CNS autoimmunity: a mechanistic approach across autoimmune encephalitis and paraneoplastic disorders.

Frank Leypoldt, Alexander Scheffold, Carina Saggau.

   PURPOSE OF REVIEW: Autoimmune encephalitis (AE), paraneoplastic neurological syndromes (PNS), and glial antibody-mediated disorders (for example, AQP4-NMOSD) are traditionally classified based on the target antigens of their respective autoantibodies. However, recent insights from immunogenomics, single-cell sequencing, and neuropathology indicate that T cell programs substantially influence disease initiation, localization, and chronicity. This review highlights three emerging dimensions of T-cell involvement - circulating exhausted-like helper T-cell memory, intrathecal T-B cooperation, and parenchymal tissue-resident cytotoxicity - that offer new perspectives on clinical and pathological features across these disorders.
RECENT FINDINGS: In AQP4-NMOSD, circulating exhausted-like CD4+ T cells may constitute a durable autoreactive memory reservoir capable of re-initiating plasmablast responses. In LGI1- and CASPR2-associated encephalitis, systemic and intrathecal CD4+ differentiation appears to support systemic antibody maturation and local plasmablast expansion, with emerging hints of some accompanying CD8+ -mediated tissue injury. In contrast, in PNS and intracellular antigen-associated AE, CD8+ T cell-mediated cytotoxicity dominates and is characterized by parenchymal CD8+ tissue-resident memory (TRM) signatures.
SUMMARY: These T-cell dimensions may provide a useful framework for understanding clinical paradoxes - such as relapse despite B-cell depletion, persistent memory dysfunction in IgG4-AE, and therapeutic inefficacy in PNS - and suggest opportunities for therapeutic strategies targeting exhausted T-cell memory, intrathecal cooperation, or TRM stability.

Keywords:  ; AQP4 neuromyelitis optica spectrum disease; autoimmune encephalitis; paraneoplastic neurologic syndromes

DOI:  https://doi.org/10.1097/WCO.0000000000001492
Nat Immunol. 2026 Apr 13.

The dual role of TOX in regulating TH1 and CD8+ T cell fate.

Yoon-Chul Kye, Vijay K Kuchroo.

DOI: https://doi.org/10.1038/s41590-026-02494-7
Exp Mol Med. 2026 Apr 13.

Metabolic oxidoreductases: central regulators of the epigenetic landscapes in stemness.

Han-Teo Lee, Jae-Seok Roe, Hong-Duk Youn.

Cell metabolism has long been recognized as a fundamental process for energy production, biomolecule synthesis, and cell survival. During transitions between stem and somatic states, central carbon metabolism is rewired with concurrent changes in chromatin regulation and gene expression. Because a specific central carbon metabolic transition occurs simultaneously during the epigenetic transition from stem cells to somatic cells or vice versa, metabolism has an important role in determining the epigenetic landscape that influences cell fate. Oxidoreductases are key enzymes that catalyze oxidation-reduction reactions during central carbon metabolism. They also have important roles in determining the metabolic flux and epigenetic landscapes by supplying epigenetic metabolites, directly shaping chromatin structures through posttranslational modifications, and acting as scaffold proteins for epigenetic complexes to affect chromatin states. In this Review, we outline emerging mechanisms by which oxidoreductases couple metabolic flux to epigenetic landscapes that maintain or dissolve stemness.

DOI: https://doi.org/10.1038/s12276-026-01687-2
bioRxiv. 2026 Apr 06. pii: 2026.04.02.716095. [Epub ahead of print]

Identity, ontogeny, and age-related changes in splenic white pulp macrophages in mouse and human spleen.

Kalyn R Thayer, Maxwell J Schleck, Yuliana V Sokolenko, Radmila A Nafikova, Zhan Yu, Ziyan Lu, Karolina J Senkow, Elsie G Bunyan, William T Plodzeen, Constance E Runyan, Rogan A Grant, Suchitra Swaminathan, Duc Phan, Hiam Abdala-Valencia, Chitaru Kurihara, Ankit Bharat, Anthony D Yang, Ryan P Merkow, Stephanie C Eisenbarth, Natania S Field, Samuel E Weinberg, Mary Carns, Harris Perlman, G R Scott Budinger, Alexander V Misharin.

The spleen contains diverse macrophage subsets that remove aged erythrocytes, prevent the dissemination of circulating pathogens, and shape the adaptive immune response 1-3 . The mouse spleen hosts red pulp macrophages (RPM), marginal zone macrophages (MZM), marginal zone metallophilic macrophages (MMM), and tingible body macrophages (TBM). However, their transcriptomic identity, ontogeny, and dynamics during aging are unknown. Furthermore, it is not known whether homologous populations of macrophages exist in the human spleen. We find that in mice, MZM and MMM are tissue-resident macrophages that maintain their population via local proliferation, while TBM are slowly replaced by circulating monocytes. Lineage tracing shows that MMM maintain the MZM pool, and that after MMM depletion, circulating monocytes restore MMM. We show that a decrease in MMM abundance in aging precedes changes in other cellular populations and splenic niches. In human spleen, we identify TBM and perifollicular zone macrophages (PFZM) as a single macrophage population homologous to MMM and MZM in mice. We show that in both mouse and human TBM become more abundant during aging. Our results suggest age-related changes in the splenic microenvironment drive changes in tissue-resident splenic macrophage populations with potential importance for the loss of immunologic function in older individuals.

DOI: https://doi.org/10.64898/2026.04.02.716095
bioRxiv. 2026 Apr 11. pii: 2026.04.08.717283. [Epub ahead of print]

Dual-Engineered Dendritic Cell Derived Small Extracellular Vesicles Couple T Cell Priming with Checkpoint Reprogramming for Synergistic Immunotherapy.

Gaeun Kim, Shiyu Wang, Runyao Zhu, Matthew J Webber, Xin Lu, Yichun Wang.

Immunotherapy has transformed cancer treatment, yet cell-based therapies remain complex and costly, and immune checkpoint blockade (ICB) agents often suffer from limited stability and poor T cell selectivity. Here, we develop an engineered dendritic cell derived small extracellular vesicle (DC sEV) nanoplatform for combinatorial immunotherapy via in situ T cell activation and checkpoint reprogramming. DC sEVs preserve intrinsic dendritic-cell immunobiology, enabling antigen presentation and potent T cell activation. We further integrate high efficiency cargo loading and membrane functionalization to selectively deliver ICB payloads to T cells, achieving dual reprogramming that sustains effector function and amplifies antitumor immunity. This approach reduced cancer cell viability to 44.05% in vitro and produced 82.12% tumor growth inhibition in vivo, establishing DC sEVs as a targeted, scalable cell-free immunotherapy platform.

DOI: https://doi.org/10.64898/2026.04.08.717283
Front Immunol. 2026 ;17 1734880

Mitochondrial dysfunction in immune cells during the perioperative period: mechanisms, emerging therapeutic strategies, and implications for multi-organ protection.

Ziyu Wang, Lu Wang, Maolin Ji, Jie Lou, Yuchuan Yuan, Yuanxu Cui, Gang Xiang, Xing Zhou.

  Mitochondrial health is increasingly recognized as a critical determinant of immune competence during the perioperative period. Surgical interventions impose unique metabolic and inflammatory stresses-such as ischemia-reperfusion injury, anesthetic exposure, and systemic inflammatory responses-that impair immune cell bioenergetics and redox balance. Dysfunctional mitochondria in neutrophils, macrophages, and T lymphocytes alter cytokine production, phagocytic activity, and antigen presentation, tipping the balance toward excessive inflammation or postoperative immunosuppression, thereby exacerbating organ injury. This review integrates current knowledge of the mechanisms linking perioperative mitochondrial dysfunction to immune dysregulation, and systematically evaluates emerging therapeutic strategies, including mitochondrial-targeted antioxidants, permeability transition pore inhibitors, metabolic reprogramming agents, mitochondrial transplantation, and gene-based interventions. By bridging experimental evidence with translational and early clinical studies in cardiac, neurological, hepatic, and renal surgeries, we argue that precise modulation of immune cell mitochondrial function represents a promising and underexplored frontier for comprehensive perioperative organ protection.

Keywords:  immune cells; immunomodulation; mitochondrial dysfunction; organ protection; perioperative period

DOI:  https://doi.org/10.3389/fimmu.2026.1734880
Clin Transl Immunology. 2026 ;15(4): e70091

Fatty acid metabolism-an emerging regulatory node in T-cell immunometabolism.

Brett Chapel Arenberg, Michael N Sack, Jing Wu.

  While the roles of glucose metabolism and tricarboxylic acid (TCA) cycle intermediates in immune regulation are well established, the contribution of fatty acid metabolism remains less well defined. In this review, we examine current knowledge on the immunomodulatory functions of fatty acid metabolism, with a particular focus on T-cell biology. We discuss the catabolic, anabolic and signalling aspects of lipid metabolism and their influence on immune function. Short-chain fatty acids modulate T-cell epigenetics through histone acetylation, thereby impacting gene expression. Medium- and long-chain fatty acids augment fatty acid oxidation (FAO), which supports the expansion and function of regulatory T-cell populations. Very-long-chain polyunsaturated fatty acids, when cleaved from the membrane, serve as precursors for both pro-inflammatory and pro-resolving signalling molecules. Additionally, de novo fatty acid synthesis contributes to membrane biogenesis and alters acetyl-CoA availability, linking lipid metabolism to epigenetic regulation. The mechanisms described above present promising opportunities to modulate inflammation through targeted therapies. In this review, we focus on emerging targets within fatty acid metabolism pathways that show potential for influencing inflammatory responses in translational models. Specifically, we review key transcription factors, metabolic enzymes and dietary interventions, while also addressing current limitations and challenges in translating these findings to clinical settings. Although studies in murine models have yielded encouraging results, substantial gaps remain-particularly in applying these metabolic strategies to human T-cell biology. We conclude by emphasising the importance of validating these targets in ex vivo human models as a critical step towards future clinical intervention.

Keywords:  T‐cell inflammation; T‐cell polarisation; fatty acid metabolism; immunometabolism

DOI:  https://doi.org/10.1002/cti2.70091
bioRxiv. 2026 Apr 06. pii: 2026.04.02.716161. [Epub ahead of print]

Human Lymph Node Cellular Senescence Atlas Reveals Age-Dependent Alteration in Germinal Center B Cell Function and Niches.

Negin Farzad, Archibald Enninful, Yao Lu, Fabio Parisi, Anthony Fung, Yumi Kwon, Yajuan Li, Margaux Labrosse, Mingyu Yang, Francesco Strino, Liang Chen, Junchen Yang, Mei Zhong, Fu Gao, Bo Tao, Joseph Cunningham, Zhiliang Bai, Haikuo Li, Fang Wang, Michael Stankewich, Dongjoo Kim, Mingze Dong, Lisa M Bramer, Keyi Li, Meera R Bhat, Evan Loe, Joseph Craft, Ljiljana Pasa-Tolic, Stephanie Halene, Lingyan Shi, Yuval Kluger, Mina L Xu, Rong Fan.

Immunosenescence, the age-associated decline in immune function, is a key feature of human aging. In human lymphoid organs, however, the specific immune cell populations that acquire senescence-associated phenotypes during aging and how they influence the surrounding tissue microenvironment remain poorly understood. A spatially resolved map of these senescence-associated immune states in human lymphoid tissues could help clarify their relationship with aging and their potential contributions to the progressive decline of immune function. Here, we integrated single-cell and spatial multi-omics to systematically characterize age-related senescence in human lymph nodes (LNs). Single-cell transcriptomics of lymphoid tissues from donors aged 18 to 100 years old identified 34 immune and stromal cell types and revealed age-associated upregulation of senescence signatures in specific populations. Spatial proteomic profiling of 99 LN sections from 51 donors (18-86 years) using high-plex immunofluorescence (∼20 million cells) mapped senescence markers (p16, p21, HMGB1, 𝛾 -H2AX) at single-cell resolution, revealing diverse senescent-like cell types ("senotypes") and a stepwise shift from extrafollicular to germinal center (GC) localization with age. Notably, we observed focal clonal-like senescence in GC B cells in older donor LNs. Spatial transcriptomics, epigenomics, and metabolic imaging of selected samples further elucidate the multi-omics signatures and underlying mechanisms of functional impairment, metabolic remodeling, and distinct regulatory programs in senescent-like GC B cells. This study presents a comprehensive spatial atlas of senescence-associated immune states in human lymph nodes, revealing cell-type-specific and spatial heterogeneity that may contribute to immunosenescence and the decline of immune function during aging.

DOI: https://doi.org/10.64898/2026.04.02.716161
bioRxiv. 2026 Apr 07. pii: 2026.04.03.715992. [Epub ahead of print]

Aging restricts maturation of CXCL13 + T follicular helper cells in human immunity.

Nathan A Bracey, Casey Beppler, Tatjana Bilich, Adrienne H Long, Elsa Sola, Aviv Barak, Timothy J Few-Cooper, Azam Mohsin, Vishnu Shankar, Vamsee Mallajosyula, Lilit Kamalyan, Robson Capasso, Shai S Shen-Orr, Mark M Davis.

A decline in specific antibody responses is a hallmark of human aging, yet the differential contributions of B and T lymphocytes and their interactions remain unclear. CXCL13 is a critical chemokine that shapes germinal center organization, but the regulation of human-specific CXCL13 + Tfh cells during aging is not known. Using human tonsil organoids, single-cell RNA sequencing, and CRISPR perturbations, we mapped age-associated changes in T follicular helper (Tfh) cells, the cell type that provides T cell "help" to B cells in germinal centers (GCs). Tonsil organoids from older donors generated weaker influenza-specific antibody responses, which we traced to Tfh cell defects rather than B cells. Single-cell profiling revealed a selective loss of mature CXCL13⁺ GC-Tfh cells accompanied by accumulation of Tfh precursor states. Trajectory analysis showed that aging arrests Tfh cell maturation at the early activated precursor transition, and CRISPR perturbations identified BACH2 and SOX4 as transcriptional regulators of differentiation reduced with age. These findings reveal a human-specific mechanism of immune aging with implications for strategies to restore humoral immunity.

DOI: https://doi.org/10.64898/2026.04.03.715992
BMC Geriatr. 2026 Apr 14.

Peripheral CD8⁺ T cell subsets and physical frailty in community-dwelling older Thai adults: the role of age and multimorbidity.

Jarupa Soongsathitanon, Ticha Homjan, Prasert Assantachai, Weerasak Muangpaisan, Chanachai Sae-Lee, Kobporn Boonnak, Tararaj Dharakul.



Keywords:  CD28 loss; CD8 T lymphocyte; Frailty; Immunosenescence; Naïve T cell; TEMRA

DOI:  https://doi.org/10.1186/s12877-026-07456-0
Aging Dis. 2026 Apr 06.

Dietary Interventions for Healthy Aging: An Epigenetic Perspective.

Xinyu Zhang, Ziyue Xie, Huimin Bian, Yu Li, Ruigong Zhu, Jia Sun.

Aging is closely associated with epigenetic alterations, including changes in DNA methylation, acetylation, and shifts in histone modification patterns, which drive cellular decline and increase susceptibility to diseases. This review examines the connection between aging-related diseases and epigenetic mechanisms and explores how dietary interventions can influence this process. We discuss the Mediterranean diet (MD), caloric restriction (CR), and the ketogenic diet (KD) as key nutritional strategies. These interventions supply essential substrates and regulate enzymes central to epigenetic remodeling, thereby affecting gene expression networks involved in inflammation, metabolism, and cellular stress responses. By correcting age related epigenetic dysregulation, such dietary patterns can slow attenuate cellular senescence and reduce the risk of chronic diseases. Current evidence supports the association between diet quality and decelerated epigenetic aging. Future research is needed to establish causality and to develop personalized nutritional approaches for promoting longevity and healthspan.

DOI: https://doi.org/10.14336/AD.2026.0333