Pub Date : 2025-12-10DOI: 10.1038/s41423-025-01373-9
Patricia Hernández-López, Caterina Riillo, Laia Gasull-Celades, Jairo G. E. Lommen, Sabine Heijhuurs, Jiali Zheng, Sascha van Bruggen, Marina Zintchenko, Simon M. Brandl, Susana Minguet, Jürgen Kuball, Dennis X. Beringer
T-cell-based therapies have shown remarkable success in combatting hematologic malignancies; however, their efficacy in solid tumors is hindered by the immunosuppressive microenvironment and restricted antigen availability. The use of chimeric costimulatory receptors (CCRs) has emerged as a strategy to improve T-cell function. However, most designs target antigens distinct from the primary antigen receptor, complicating their application across heterogeneous tumors. Here, we characterized the molecular requirements for a platform enabling costimulation in engineered T cells on the basis of dual targeting of a single antigen via a TCR and a CCR. We applied this strategy to the stress ligand BTN3A, which is broadly expressed in solid tumors and is a part of the antigen complex recognized by the γ9δ2TCR. Through structural modeling, alanine scanning, and antibody screening, we determined that 103-4-1BB, a BTN3A-specific CCR, bound to an epitope on BTN3A that was distinct from the γ9δ2TCR epitope. This epitope separation is critical for enabling synergistic coengagement of a single antigen, and the resulting increase in T-cell activation requires both γ9δ2TCR signaling and the trans-acting functionality of the anti-BTN3A-CCR. Moreover, the extracellular domain of 103-4-1BB stabilized T-cell–tumor cell interactions and increased γ9δ2TCR sensitivity, whereas its intracellular 4-1BB signaling domain drove robust proliferation, improved T-cell fitness, and mediated potent tumor control in vivo. Notably, cis-binding of the CCR to BTN3A on engineered T cells promoted survival in the absence of tumor cells, while transbinding to tumor-expressed BTN3A was required for infiltration, tumor clearance, and memory formation. These findings establish a modular framework for designing cis/trans-active CCRs that enhance T-cell function through single-antigen dual engagement, enabling broadly applicable strategies to improve solid tumor immunotherapy.
{"title":"Cis- and trans-binding chimeric costimulatory receptors enhance T-cell fitness and tumor control","authors":"Patricia Hernández-López, Caterina Riillo, Laia Gasull-Celades, Jairo G. E. Lommen, Sabine Heijhuurs, Jiali Zheng, Sascha van Bruggen, Marina Zintchenko, Simon M. Brandl, Susana Minguet, Jürgen Kuball, Dennis X. Beringer","doi":"10.1038/s41423-025-01373-9","DOIUrl":"10.1038/s41423-025-01373-9","url":null,"abstract":"T-cell-based therapies have shown remarkable success in combatting hematologic malignancies; however, their efficacy in solid tumors is hindered by the immunosuppressive microenvironment and restricted antigen availability. The use of chimeric costimulatory receptors (CCRs) has emerged as a strategy to improve T-cell function. However, most designs target antigens distinct from the primary antigen receptor, complicating their application across heterogeneous tumors. Here, we characterized the molecular requirements for a platform enabling costimulation in engineered T cells on the basis of dual targeting of a single antigen via a TCR and a CCR. We applied this strategy to the stress ligand BTN3A, which is broadly expressed in solid tumors and is a part of the antigen complex recognized by the γ9δ2TCR. Through structural modeling, alanine scanning, and antibody screening, we determined that 103-4-1BB, a BTN3A-specific CCR, bound to an epitope on BTN3A that was distinct from the γ9δ2TCR epitope. This epitope separation is critical for enabling synergistic coengagement of a single antigen, and the resulting increase in T-cell activation requires both γ9δ2TCR signaling and the trans-acting functionality of the anti-BTN3A-CCR. Moreover, the extracellular domain of 103-4-1BB stabilized T-cell–tumor cell interactions and increased γ9δ2TCR sensitivity, whereas its intracellular 4-1BB signaling domain drove robust proliferation, improved T-cell fitness, and mediated potent tumor control in vivo. Notably, cis-binding of the CCR to BTN3A on engineered T cells promoted survival in the absence of tumor cells, while transbinding to tumor-expressed BTN3A was required for infiltration, tumor clearance, and memory formation. These findings establish a modular framework for designing cis/trans-active CCRs that enhance T-cell function through single-antigen dual engagement, enabling broadly applicable strategies to improve solid tumor immunotherapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"79-93"},"PeriodicalIF":19.8,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-08DOI: 10.1038/s41423-025-01371-x
Ying Wang, Shiyu Zhang, Yang Yang, Yimei Wang, Yingxin Zhang, Ming Liu, Xin Zeng, Ning Ji, Silu Sun, Chunjie Li, Yuwei Zhao, Xikun Zhou, Qianming Chen, Jing Li
Cancer cell-derived exosomes have been demonstrated to be effective as intercellular signal transmitters. PA28γ is known to be highly upregulated in cancers, but its specific role in the microenvironment remains unclear. Here, we demonstrated that PA28γ is loaded in exosomes released from head and neck squamous cell carcinoma (HNSCC) cells. Exosomal PA28γ is internalized by T cells, subsequently weakening their cytotoxic functions and increasing the expression of CD25 and LAG-3. Using a tumor orthotopic transplant model constructed with PA28γ−/− mice, we found that T cells could take up PA28γ from tumor cells. Mass cytometry (CyTOF) analysis indicated that knockdown of PA28γ reduced the infiltration of CD25+ and LAG-3+ T cells. Importantly, high-PA28γ-expressing tumors are more responsive to CD25 and LAG-3 immune checkpoint therapy than low-PA28γ-expressing tumors in vivo. Mechanically, exosomal PA28γ enhanced T-cell exhaustion by degrading BCLAF1 after it was internalized. HNSCC cohort analysis revealed that the expression of PA28γ was positively correlated with the infiltration of CD25+ and LAG-3+ T cells and that high levels of these markers could predict a poor prognosis. In summary, exosomal PA28γ induces a T-cell exhaustion phenotype by inhibiting their tumor-killing ability, promoting malignant progression via the PA28γ/BCLAF1/CD25&LAG-3 pathway. These findings reveal a novel cell‒cell interaction between tumors and T cells in the HNSCC microenvironment.
{"title":"PA28γ-containing tumor-derived exosomes promote T-cell dysfunction in head and neck squamous cell carcinoma","authors":"Ying Wang, Shiyu Zhang, Yang Yang, Yimei Wang, Yingxin Zhang, Ming Liu, Xin Zeng, Ning Ji, Silu Sun, Chunjie Li, Yuwei Zhao, Xikun Zhou, Qianming Chen, Jing Li","doi":"10.1038/s41423-025-01371-x","DOIUrl":"10.1038/s41423-025-01371-x","url":null,"abstract":"Cancer cell-derived exosomes have been demonstrated to be effective as intercellular signal transmitters. PA28γ is known to be highly upregulated in cancers, but its specific role in the microenvironment remains unclear. Here, we demonstrated that PA28γ is loaded in exosomes released from head and neck squamous cell carcinoma (HNSCC) cells. Exosomal PA28γ is internalized by T cells, subsequently weakening their cytotoxic functions and increasing the expression of CD25 and LAG-3. Using a tumor orthotopic transplant model constructed with PA28γ−/− mice, we found that T cells could take up PA28γ from tumor cells. Mass cytometry (CyTOF) analysis indicated that knockdown of PA28γ reduced the infiltration of CD25+ and LAG-3+ T cells. Importantly, high-PA28γ-expressing tumors are more responsive to CD25 and LAG-3 immune checkpoint therapy than low-PA28γ-expressing tumors in vivo. Mechanically, exosomal PA28γ enhanced T-cell exhaustion by degrading BCLAF1 after it was internalized. HNSCC cohort analysis revealed that the expression of PA28γ was positively correlated with the infiltration of CD25+ and LAG-3+ T cells and that high levels of these markers could predict a poor prognosis. In summary, exosomal PA28γ induces a T-cell exhaustion phenotype by inhibiting their tumor-killing ability, promoting malignant progression via the PA28γ/BCLAF1/CD25&LAG-3 pathway. These findings reveal a novel cell‒cell interaction between tumors and T cells in the HNSCC microenvironment.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"63-78"},"PeriodicalIF":19.8,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mammalian sterile-20-like kinase 1 (MST1) is a core component of the Hippo signaling pathway. A previous study of 24 patients with MST1 deficiency revealed that more than half of the patients presented symptoms of airway hyperresponsiveness and atopic dermatitis. We also found significantly reduced MST1 expression in patients with allergies and in mouse models of allergic asthma, suggesting that aberrant MST1 expression may be broadly relevant to allergic diseases. However, the specific mechanism by which MST1 may be related to allergic disorders has remained unclear. In our study, Mst1-/- mice displayed exacerbated IgE-mediated allergic responses, including passive systemic and cutaneous anaphylaxis. More intriguingly, mast cell-deficient KitW-sh/W-sh mice reconstituted with Mst1-/- bone marrow-derived mast cells (BMMCs) also presented aggravated IgE-mediated hypersensitivity reactions and mast cell-dependent asthma. MST1 deficiency notably promoted inflammatory cytokine production, cell degranulation, and intracellular calcium mobilization in FcεRI-stimulated BMMCs. Mechanistically, MST1 facilitates SRC homology domain-containing tyrosine phosphatase-1 (SHP-1)-mediated dephosphorylation of LCK/YES-related protein tyrosine kinase (LYN) at Y397 to repress FcɛRI signaling. Coimmunoprecipitation studies revealed that MST1 acts as a scaffold molecule to enhance the interaction between SHP-1 and LYN in a kinase activity-independent manner. Two patient-derived mutants presented significantly reduced intracellular protein expression levels and impaired LYN-SHP-1 interactions. Our study reveals a noncanonical role of MST1 in maintaining immune homeostasis by preventing mast cell-mediated hypersensitivity. This likely explains the increased susceptibility to allergic diseases in MST1-deficient patients.
{"title":"MST1 bridges LYN and SHP-1 to suppress FcεRI-mediated mast cell activation and allergic responses","authors":"Mengyao Li, Huihan Li, Wenlong Lin, Lin Tong, Lingman Dai, Qiannan Zhao, Mengting Hu, Zhimin Chen, Yiting Zhou, Qingqing Wang, Yuanyuan Zhang","doi":"10.1038/s41423-025-01374-8","DOIUrl":"10.1038/s41423-025-01374-8","url":null,"abstract":"Mammalian sterile-20-like kinase 1 (MST1) is a core component of the Hippo signaling pathway. A previous study of 24 patients with MST1 deficiency revealed that more than half of the patients presented symptoms of airway hyperresponsiveness and atopic dermatitis. We also found significantly reduced MST1 expression in patients with allergies and in mouse models of allergic asthma, suggesting that aberrant MST1 expression may be broadly relevant to allergic diseases. However, the specific mechanism by which MST1 may be related to allergic disorders has remained unclear. In our study, Mst1-/- mice displayed exacerbated IgE-mediated allergic responses, including passive systemic and cutaneous anaphylaxis. More intriguingly, mast cell-deficient KitW-sh/W-sh mice reconstituted with Mst1-/- bone marrow-derived mast cells (BMMCs) also presented aggravated IgE-mediated hypersensitivity reactions and mast cell-dependent asthma. MST1 deficiency notably promoted inflammatory cytokine production, cell degranulation, and intracellular calcium mobilization in FcεRI-stimulated BMMCs. Mechanistically, MST1 facilitates SRC homology domain-containing tyrosine phosphatase-1 (SHP-1)-mediated dephosphorylation of LCK/YES-related protein tyrosine kinase (LYN) at Y397 to repress FcɛRI signaling. Coimmunoprecipitation studies revealed that MST1 acts as a scaffold molecule to enhance the interaction between SHP-1 and LYN in a kinase activity-independent manner. Two patient-derived mutants presented significantly reduced intracellular protein expression levels and impaired LYN-SHP-1 interactions. Our study reveals a noncanonical role of MST1 in maintaining immune homeostasis by preventing mast cell-mediated hypersensitivity. This likely explains the increased susceptibility to allergic diseases in MST1-deficient patients.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"48-62"},"PeriodicalIF":19.8,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-03DOI: 10.1038/s41423-025-01366-8
Jaewoo Park, SangJoon Lee
{"title":"Dysregulation of innate immune sensors and autoinflammation: insights from an NLRC4 mouse AIFEC model","authors":"Jaewoo Park, SangJoon Lee","doi":"10.1038/s41423-025-01366-8","DOIUrl":"10.1038/s41423-025-01366-8","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"120-122"},"PeriodicalIF":19.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1038/s41423-025-01369-5
Emma Miglierina, Julien Bouder, Delfina Ordanoska, Maïwenn Pineau, Simon Léonard, Anaïs Schavgoulidze, Gwenaëlle Quéré, Maeva Le Goff, Maé Bouchet, Steve Alexandre Genebrier, Samuel Bastos Serra Trinca, Laurent Deleurme, Céline Monvoisin, Laure Derrier, Charles Dumontet, Laurent Delpy, Jérôme Moreaux, Jill Corre, Michel Cogné, Brice Laffleur
DIS3 is the main catalytic subunit of the nuclear RNA exosome, a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates. In mice, DIS3 is essential for genomic rearrangements during B cell development, but its role in terminal plasma cell (PC) differentiation has not been explored. Although DIS3 gene alterations are frequent in multiple myeloma (MM), a PC malignancy, their molecular impact remains poorly understood. In this study, we developed an antisense oligonucleotide strategy to knock down DIS3 expression in a well-characterized model of human PC differentiation. Reducing DIS3 expression systematically led to decreased B cell proliferation and impaired PC differentiation with lower levels of switched immunoglobulin secretion. Transcriptome analyses confirmed alterations in the proliferation and differentiation programs, alongside an accumulation of noncoding RNAs. Notably, centromere-associated noncoding RNAs were highly sensitive to DIS3 activity, and their accumulation in DIS3-deficient cells, either as transcripts or DNA-associated RNAs, correlated with the mislocalization of the centromere-specific histone variant CENP-A. We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells, in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients. Together, these results underscore the essential role of DIS3 in regulating B cell proliferation, DNA recombination, and physiological or malignant PC differentiation in humans.
{"title":"DIS3 licenses B cells for plasma cell differentiation in humans","authors":"Emma Miglierina, Julien Bouder, Delfina Ordanoska, Maïwenn Pineau, Simon Léonard, Anaïs Schavgoulidze, Gwenaëlle Quéré, Maeva Le Goff, Maé Bouchet, Steve Alexandre Genebrier, Samuel Bastos Serra Trinca, Laurent Deleurme, Céline Monvoisin, Laure Derrier, Charles Dumontet, Laurent Delpy, Jérôme Moreaux, Jill Corre, Michel Cogné, Brice Laffleur","doi":"10.1038/s41423-025-01369-5","DOIUrl":"10.1038/s41423-025-01369-5","url":null,"abstract":"DIS3 is the main catalytic subunit of the nuclear RNA exosome, a complex playing a crucial role in RNA processing and the degradation of various noncoding RNA substrates. In mice, DIS3 is essential for genomic rearrangements during B cell development, but its role in terminal plasma cell (PC) differentiation has not been explored. Although DIS3 gene alterations are frequent in multiple myeloma (MM), a PC malignancy, their molecular impact remains poorly understood. In this study, we developed an antisense oligonucleotide strategy to knock down DIS3 expression in a well-characterized model of human PC differentiation. Reducing DIS3 expression systematically led to decreased B cell proliferation and impaired PC differentiation with lower levels of switched immunoglobulin secretion. Transcriptome analyses confirmed alterations in the proliferation and differentiation programs, alongside an accumulation of noncoding RNAs. Notably, centromere-associated noncoding RNAs were highly sensitive to DIS3 activity, and their accumulation in DIS3-deficient cells, either as transcripts or DNA-associated RNAs, correlated with the mislocalization of the centromere-specific histone variant CENP-A. We finally observed reduced physiological DNA recombination and somatic hypermutation but increased genomic instability in DIS3-deficient cells, in agreement with the higher levels of IGH translocations observed in our large cohort of DIS3-mutant MM patients. Together, these results underscore the essential role of DIS3 in regulating B cell proliferation, DNA recombination, and physiological or malignant PC differentiation in humans.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"23 1","pages":"31-47"},"PeriodicalIF":19.8,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01369-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-21DOI: 10.1038/s41423-025-01368-6
Takashi Shimizu, Marco Prinz
Microglia, the resident immune cells of the central nervous system, exhibit conserved developmental origins and core molecular signatures across vertebrate species, highlighting their crucial importance in the central nervous system. While homeostatic microglia maintain similar functions during phylogeny—such as immune surveillance, debris clearance, and synaptic pruning—their morphology, gene expression, and responses to stimuli remarkably vary by species. These differences reflect evolutionary divergence shaped by factors such as lifespan, regenerative potential, and immune architecture. This review integrates current findings from basic vertebrates such as zebrafish, rodents, and nonhuman primates with those from humans to highlight conserved and divergent aspects of microglial biology throughout evolution. Integrating these evolutionary differences is crucial for translating mechanistic insights across model organisms and advancing microglia-targeted therapies for neurological disorders.
{"title":"Microglia across evolution: from conserved origins to functional divergence","authors":"Takashi Shimizu, Marco Prinz","doi":"10.1038/s41423-025-01368-6","DOIUrl":"10.1038/s41423-025-01368-6","url":null,"abstract":"Microglia, the resident immune cells of the central nervous system, exhibit conserved developmental origins and core molecular signatures across vertebrate species, highlighting their crucial importance in the central nervous system. While homeostatic microglia maintain similar functions during phylogeny—such as immune surveillance, debris clearance, and synaptic pruning—their morphology, gene expression, and responses to stimuli remarkably vary by species. These differences reflect evolutionary divergence shaped by factors such as lifespan, regenerative potential, and immune architecture. This review integrates current findings from basic vertebrates such as zebrafish, rodents, and nonhuman primates with those from humans to highlight conserved and divergent aspects of microglial biology throughout evolution. Integrating these evolutionary differences is crucial for translating mechanistic insights across model organisms and advancing microglia-targeted therapies for neurological disorders.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1533-1548"},"PeriodicalIF":19.8,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01368-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1038/s41423-025-01370-y
Alice Werynski, Chun-Xiao Li, Yujing Hao, Andrea Cerutti, Kang Chen
{"title":"Author Correction: Not marginal but central: type I interferons unleash marginal zone B cells in Sjögren’s disease","authors":"Alice Werynski, Chun-Xiao Li, Yujing Hao, Andrea Cerutti, Kang Chen","doi":"10.1038/s41423-025-01370-y","DOIUrl":"10.1038/s41423-025-01370-y","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1648-1648"},"PeriodicalIF":19.8,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01370-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145548612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Intracerebral hemorrhage (ICH) causes hematoma formation, leading to PHE, which is associated with leukocyte mobilization and increased inflammation at the site of brain injury. However, the fate of accumulated leukocytes within the hematoma and their impact on PHE expansion remain unknown. We performed single-cell immune profiling of hematoma cells from patients with acute ICH and reported a distinct phenotypic transformation of CD8+ T cells within the hematoma during the first 24 h after onset. In addition to enhanced IFN-γ production and migration capacity, these CD8+ T cells displayed remarkable glycolytic signatures. The metabolic fitness and functional reprogramming of hematomal CD8+ T cells are associated with the transcription factor FOXO1. Single-cell profiling of brain-infiltrating CD8+ T cells within the perihematomal tissues of ICH patients and cell culture assays revealed their capacity to activate microglia via the production of IFN-γ. Furthermore, the removal of hematomal CD8+ T cells reduced neuroinflammation, PHE expansion and neurological deficits in ICH mice. Thus, CD8+ T cells undergo metabolic and functional reprogramming within the hematoma during the acute phase of ICH, which contributes to PHE formation and neurological deterioration.
{"title":"FOXO1-driven metabolic reprogramming of hematomal CD8+ T cells drives the expansion of perihematomal edema following intracerebral hemorrhage","authors":"Jie Lin, Honglei Ren, Youliang Wang, Hanzhi Yu, Zhili Chen, Xintong Yu, Zhuyu Gao, Yan Zheng, Quanhong Wu, Yizhe Zhang, Qijian Lin, Rui Li, Decai Tian, Zhigang Cai, Qiang Liu, Ying Fu","doi":"10.1038/s41423-025-01363-x","DOIUrl":"10.1038/s41423-025-01363-x","url":null,"abstract":"Intracerebral hemorrhage (ICH) causes hematoma formation, leading to PHE, which is associated with leukocyte mobilization and increased inflammation at the site of brain injury. However, the fate of accumulated leukocytes within the hematoma and their impact on PHE expansion remain unknown. We performed single-cell immune profiling of hematoma cells from patients with acute ICH and reported a distinct phenotypic transformation of CD8+ T cells within the hematoma during the first 24 h after onset. In addition to enhanced IFN-γ production and migration capacity, these CD8+ T cells displayed remarkable glycolytic signatures. The metabolic fitness and functional reprogramming of hematomal CD8+ T cells are associated with the transcription factor FOXO1. Single-cell profiling of brain-infiltrating CD8+ T cells within the perihematomal tissues of ICH patients and cell culture assays revealed their capacity to activate microglia via the production of IFN-γ. Furthermore, the removal of hematomal CD8+ T cells reduced neuroinflammation, PHE expansion and neurological deficits in ICH mice. Thus, CD8+ T cells undergo metabolic and functional reprogramming within the hematoma during the acute phase of ICH, which contributes to PHE formation and neurological deterioration.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 12","pages":"1629-1641"},"PeriodicalIF":19.8,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01363-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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