Splenic sympathetic activity critically modulates peripheral immunity after ischemic stroke, thus intervention in spleen sympathetic activity represents a promising therapeutic strategy for stroke. However, the mechanisms underlying spleen-brain-immune axis communication remain poorly understood. Here, we utilized a surgical denervation protocol to perform splenic sympathetic denervation (SDN), which significantly attenuated brain injury following stroke. Through single-cell RNA sequencing, we identified a novel GZMK+CD8+CD27+CCR7+ T-cell subset in patients with acute ischemic stroke (AIS), which we designated stroke-associated T (Tsa) cells. The expansion of Tsa cells was positively correlated with the severity of clinical symptoms and was driven by the splenic sympathetic nervous system. Stroke-induced sympathetic activation triggers the release of splenic norepinephrine (NE), which preferentially signals through ADRB2 on Tsa cells to promote their mobilization. Additionally, ischemic injury induces endothelial cell-specific expression of CCL19, which chemoattracts Tsa cells into the brain parenchyma via their cognate CCR7 receptor, exacerbating neuroinflammatory injury and neurological deficits in a transient middle cerebral artery occlusion (tMCAO) mouse model. We developed a CCR7-targeting peptide to disrupt this chemotactic axis and reduce T-cell infiltration, thereby mitigating brain injury. Our findings highlight SDN as a promising therapeutic strategy to attenuate ischemia‒reperfusion injury and suggest its potential as an adjunctive therapy for reperfusion treatment in AIS patients.
{"title":"CD8+GZMK+CD27+CCR7+ T cells mobilized by splenic sympathetic nerves aggravate brain ischemia‒reperfusion injury via CCL19-positive endothelial cells","authors":"Ying Bai, Hui Ren, Shuo Leng, Mengqin Yuan, YiXin Jiang, Shenyang Zhang, Yu Wang, Minzi Ju, Zhi Wang, Wen Xi, Lian Xu, Bingjing Zheng, Daxing Li, Xinchen Huo, Tianhao Zhu, Beicheng Zhang, Ling Shen, Yuan Zhang, Wei Jiang, John H. Zhang, Bing Han, Honghong Yao","doi":"10.1038/s41423-025-01311-9","DOIUrl":"10.1038/s41423-025-01311-9","url":null,"abstract":"Splenic sympathetic activity critically modulates peripheral immunity after ischemic stroke, thus intervention in spleen sympathetic activity represents a promising therapeutic strategy for stroke. However, the mechanisms underlying spleen-brain-immune axis communication remain poorly understood. Here, we utilized a surgical denervation protocol to perform splenic sympathetic denervation (SDN), which significantly attenuated brain injury following stroke. Through single-cell RNA sequencing, we identified a novel GZMK+CD8+CD27+CCR7+ T-cell subset in patients with acute ischemic stroke (AIS), which we designated stroke-associated T (Tsa) cells. The expansion of Tsa cells was positively correlated with the severity of clinical symptoms and was driven by the splenic sympathetic nervous system. Stroke-induced sympathetic activation triggers the release of splenic norepinephrine (NE), which preferentially signals through ADRB2 on Tsa cells to promote their mobilization. Additionally, ischemic injury induces endothelial cell-specific expression of CCL19, which chemoattracts Tsa cells into the brain parenchyma via their cognate CCR7 receptor, exacerbating neuroinflammatory injury and neurological deficits in a transient middle cerebral artery occlusion (tMCAO) mouse model. We developed a CCR7-targeting peptide to disrupt this chemotactic axis and reduce T-cell infiltration, thereby mitigating brain injury. Our findings highlight SDN as a promising therapeutic strategy to attenuate ischemia‒reperfusion injury and suggest its potential as an adjunctive therapy for reperfusion treatment in AIS patients.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 9","pages":"1061-1076"},"PeriodicalIF":19.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636324","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 : 2025-07-10DOI: 10.1038/s41423-025-01321-7
Dawei Zou, Xian C. Li, Wenhao Chen
T cells often acquire diverse phenotypes and functional states following activation. CD4+ T cells are traditionally classified into distinct effector subsets, such as Th1, Th2, Th17, and Tfh, on the basis of their cytokine profiles and functional roles. While this framework has advanced our understanding of adaptive immunity, it has limitations in explaining the persistence of T-cell responses in settings of autoimmunity and transplant rejection, in contrast to its limited efficacy in cancer. Moving beyond this subset-based framework, recent studies have revealed that stemness and adaptation are fundamental to CD4+ T-cell fate and function. Central to this new understanding is the TCF1+ stem-like CD4+ T-cell population, which emerges early after activation and serves as a reservoir for effector differentiation. These cells dynamically integrate environmental cues to direct effector differentiation and shape functional outcomes at target tissue sites, a process we define as clonal adaptation. By balancing self-renewal with effector differentiation, stem-like CD4+ T cells continue to replenish short-lived effector cells to sustain autoimmunity, transplant rejection, chronic infections, and allergic diseases. However, under tolerogenic conditions or within the tumor microenvironment, these cells often fail to differentiate into effectors, instead entering dysfunctional states or regulatory T-cell differentiation. Targeting stem-like CD4+ T cells offers great therapeutic potential: disrupting their persistence could mitigate autoimmune pathology and transplant rejection, whereas enhancing their effector capacity could improve antitumor immunity.
{"title":"Beyond T-cell subsets: stemness and adaptation redefining immunity and immunotherapy","authors":"Dawei Zou, Xian C. Li, Wenhao Chen","doi":"10.1038/s41423-025-01321-7","DOIUrl":"10.1038/s41423-025-01321-7","url":null,"abstract":"T cells often acquire diverse phenotypes and functional states following activation. CD4+ T cells are traditionally classified into distinct effector subsets, such as Th1, Th2, Th17, and Tfh, on the basis of their cytokine profiles and functional roles. While this framework has advanced our understanding of adaptive immunity, it has limitations in explaining the persistence of T-cell responses in settings of autoimmunity and transplant rejection, in contrast to its limited efficacy in cancer. Moving beyond this subset-based framework, recent studies have revealed that stemness and adaptation are fundamental to CD4+ T-cell fate and function. Central to this new understanding is the TCF1+ stem-like CD4+ T-cell population, which emerges early after activation and serves as a reservoir for effector differentiation. These cells dynamically integrate environmental cues to direct effector differentiation and shape functional outcomes at target tissue sites, a process we define as clonal adaptation. By balancing self-renewal with effector differentiation, stem-like CD4+ T cells continue to replenish short-lived effector cells to sustain autoimmunity, transplant rejection, chronic infections, and allergic diseases. However, under tolerogenic conditions or within the tumor microenvironment, these cells often fail to differentiate into effectors, instead entering dysfunctional states or regulatory T-cell differentiation. Targeting stem-like CD4+ T cells offers great therapeutic potential: disrupting their persistence could mitigate autoimmune pathology and transplant rejection, whereas enhancing their effector capacity could improve antitumor immunity.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 9","pages":"957-974"},"PeriodicalIF":19.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599536","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 : 2025-07-10DOI: 10.1038/s41423-025-01317-3
Mohammad H. Hasan, Lalit K. Beura
{"title":"Monocyte-derived TGF-β shapes memory CD8+ T cells","authors":"Mohammad H. Hasan, Lalit K. Beura","doi":"10.1038/s41423-025-01317-3","DOIUrl":"10.1038/s41423-025-01317-3","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"949-950"},"PeriodicalIF":19.8,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599537","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 : 2025-07-09DOI: 10.1038/s41423-025-01316-4
Kun Peng, Xiaoxue Zhao, Yang-Xin Fu, Yong Liang
Therapeutic cancer vaccines aim to expand and activate antigen-specific T cells for the targeted elimination of cancer cells. While early clinical trials faced challenges due to suboptimal antigen-specific T-cell activation, recent advancements in antigen discovery and vaccine platform engineering have revitalized the field. This review provides a comprehensive overview of key tumor antigens, including tumor-associated antigens, viral oncoprotein antigens, neoantigens, and cryptic antigens, with a focus on their immunogenicity and therapeutic potential. Advances in our understanding of traditional cancer vaccination targets, in conjunction with the timely identification of novel antigen epitopes, have facilitated the strategic selection of vaccination targets. We also discuss the evolution of cancer vaccine platforms—spanning peptide-based formulations to advanced mRNA vectors—emphasizing innovative strategies to optimize antigen delivery efficiency and adjuvant effects. Efficient antigen delivery and adjuvant selection overcome immune tolerance and tumor-induced immunosuppression. Furthermore, we examine recent clinical trial data and emerging combination approaches that integrate cancer vaccines with other immunotherapies to increase efficacy. While significant progress has been made, challenges remain in improving vaccine-induced T-cell responses, overcoming immune suppression, and translating these advances into effective clinical interventions. Addressing these hurdles will be critical for realizing the full potential of cancer vaccines in immunotherapy.
{"title":"Eliciting antitumor immunity via therapeutic cancer vaccines","authors":"Kun Peng, Xiaoxue Zhao, Yang-Xin Fu, Yong Liang","doi":"10.1038/s41423-025-01316-4","DOIUrl":"10.1038/s41423-025-01316-4","url":null,"abstract":"Therapeutic cancer vaccines aim to expand and activate antigen-specific T cells for the targeted elimination of cancer cells. While early clinical trials faced challenges due to suboptimal antigen-specific T-cell activation, recent advancements in antigen discovery and vaccine platform engineering have revitalized the field. This review provides a comprehensive overview of key tumor antigens, including tumor-associated antigens, viral oncoprotein antigens, neoantigens, and cryptic antigens, with a focus on their immunogenicity and therapeutic potential. Advances in our understanding of traditional cancer vaccination targets, in conjunction with the timely identification of novel antigen epitopes, have facilitated the strategic selection of vaccination targets. We also discuss the evolution of cancer vaccine platforms—spanning peptide-based formulations to advanced mRNA vectors—emphasizing innovative strategies to optimize antigen delivery efficiency and adjuvant effects. Efficient antigen delivery and adjuvant selection overcome immune tolerance and tumor-induced immunosuppression. Furthermore, we examine recent clinical trial data and emerging combination approaches that integrate cancer vaccines with other immunotherapies to increase efficacy. While significant progress has been made, challenges remain in improving vaccine-induced T-cell responses, overcoming immune suppression, and translating these advances into effective clinical interventions. Addressing these hurdles will be critical for realizing the full potential of cancer vaccines in immunotherapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"840-868"},"PeriodicalIF":19.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12311208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590568","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 : 2025-07-08DOI: 10.1038/s41423-025-01320-8
Xiangxiang Jiang, Mei-Rong Du, Min Li, Hongmei Wang
{"title":"Author Correction: Three macrophage subsets are identified in the uterus during early human pregnancy","authors":"Xiangxiang Jiang, Mei-Rong Du, Min Li, Hongmei Wang","doi":"10.1038/s41423-025-01320-8","DOIUrl":"10.1038/s41423-025-01320-8","url":null,"abstract":"","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"954-956"},"PeriodicalIF":19.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12311049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583184","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 : 2025-07-04DOI: 10.1038/s41423-025-01314-6
Qi Zhu, Jiajia Li, Nan Liu, Lu Han, Zhiqiang Wu, Yao Wang, Xin Lin, Jianshu Wei, Weidong Han
CAR-T-cell therapy has made significant strides in treating hematological malignancies, yet its efficacy is often hampered by suboptimal T-cell functionality, marked by weak antitumor capabilities and a lack of durability. The immunological synapse, a key determinant of T-cell function, is influenced by the CD58-CD2 axis. The dynamic regulation of CD2 expression on T cells impacts the quality of CAR-mediated immunological synapses, affecting CAR-T-cell functional outcomes and differentiation. Our study demonstrated that CD2 expression levels are closely linked to the quality of immunological synapses formed by CAR-T cells and their antitumor potency. Exogenous CD2 supplementation enhances the ability of CAR-T cells to form high-quality synapses, reduces T-cell exhaustion, and increases sustained antitumor efficacy. Additionally, ectopic CD2 expression increases CAR-T-cell sensitivity to low-density antigens. Thus, replenishing CD2 in CAR-T cells is a promising strategy to increase the therapeutic efficacy of CAR-T-cell therapy.
car - t细胞疗法在治疗血液系统恶性肿瘤方面取得了重大进展，但其疗效往往受到t细胞功能不理想的阻碍，其特点是抗肿瘤能力弱且缺乏持久性。免疫突触是t细胞功能的关键决定因素，受CD58-CD2轴的影响。T细胞上CD2表达的动态调控影响car介导的免疫突触的质量，影响car -T细胞的功能结局和分化。我们的研究表明，CD2表达水平与CAR-T细胞形成的免疫突触的质量及其抗肿瘤能力密切相关。补充外源性CD2可增强CAR-T细胞形成高质量突触的能力，减少t细胞耗竭，并增加持续的抗肿瘤疗效。此外，异位CD2表达增加了car - t细胞对低密度抗原的敏感性。因此，在CAR-T细胞中补充CD2是提高CAR-T细胞治疗效果的一种有希望的策略。
{"title":"CD2 augmentation enhances CAR-T-cell efficacy via immunological synapse remodeling and T-cell exhaustion mitigation","authors":"Qi Zhu, Jiajia Li, Nan Liu, Lu Han, Zhiqiang Wu, Yao Wang, Xin Lin, Jianshu Wei, Weidong Han","doi":"10.1038/s41423-025-01314-6","DOIUrl":"10.1038/s41423-025-01314-6","url":null,"abstract":"CAR-T-cell therapy has made significant strides in treating hematological malignancies, yet its efficacy is often hampered by suboptimal T-cell functionality, marked by weak antitumor capabilities and a lack of durability. The immunological synapse, a key determinant of T-cell function, is influenced by the CD58-CD2 axis. The dynamic regulation of CD2 expression on T cells impacts the quality of CAR-mediated immunological synapses, affecting CAR-T-cell functional outcomes and differentiation. Our study demonstrated that CD2 expression levels are closely linked to the quality of immunological synapses formed by CAR-T cells and their antitumor potency. Exogenous CD2 supplementation enhances the ability of CAR-T cells to form high-quality synapses, reduces T-cell exhaustion, and increases sustained antitumor efficacy. Additionally, ectopic CD2 expression increases CAR-T-cell sensitivity to low-density antigens. Thus, replenishing CD2 in CAR-T cells is a promising strategy to increase the therapeutic efficacy of CAR-T-cell therapy.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 8","pages":"935-948"},"PeriodicalIF":19.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12311108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564634","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 : 2025-07-02DOI: 10.1038/s41423-025-01312-8
Milad Rezvani
The liver hosts a variety of immune cells while creating a tolerogenic environment under homeostatic conditions. However, most chronic liver diseases shift toward inflammation over time. Understanding and intercepting the crosstalk between various immune cells and liver tissue is crucial, as it is often the rate-limiting factor in preclinical drug development. Owing to significant interspecies differences in liver immunology, human models, such as classical cocultures or organogenesis-inspired liver organoids with immune compartments, are becoming essential for advancing the field. Therefore, this review evaluates human-specific models of hepatic-immune crosstalk and assesses a range of models from basic 2D cultures to microphysiological systems (MPSs) and advanced multitissue organoids. It serves as a guide for experimentalists to identify suitable approaches. For example, traditional cocultures offer robustness, reductionist approaches, and modularity but have limited spatial fidelity and cell heterogeneity. In contrast, multitissue organoids inspired by mammalian ontogeny are created from pluripotent stem cells and integrate multiple tissue niche-constituting cells, which include Kupffer-like cells. In conclusion, this review discusses progress in human liver immunology modeling and highlights limitations and numerous untapped opportunities. These include the potential to model in vitro autoimmunity and more complex myeloid inflammatory responses, incorporating contributions from embryonic tissue and bone marrow. Additionally, future in vitro models may include hard-to-culture populations such as neutrophils.
{"title":"Human liver immunology: from in vitro models to new insights","authors":"Milad Rezvani","doi":"10.1038/s41423-025-01312-8","DOIUrl":"10.1038/s41423-025-01312-8","url":null,"abstract":"The liver hosts a variety of immune cells while creating a tolerogenic environment under homeostatic conditions. However, most chronic liver diseases shift toward inflammation over time. Understanding and intercepting the crosstalk between various immune cells and liver tissue is crucial, as it is often the rate-limiting factor in preclinical drug development. Owing to significant interspecies differences in liver immunology, human models, such as classical cocultures or organogenesis-inspired liver organoids with immune compartments, are becoming essential for advancing the field. Therefore, this review evaluates human-specific models of hepatic-immune crosstalk and assesses a range of models from basic 2D cultures to microphysiological systems (MPSs) and advanced multitissue organoids. It serves as a guide for experimentalists to identify suitable approaches. For example, traditional cocultures offer robustness, reductionist approaches, and modularity but have limited spatial fidelity and cell heterogeneity. In contrast, multitissue organoids inspired by mammalian ontogeny are created from pluripotent stem cells and integrate multiple tissue niche-constituting cells, which include Kupffer-like cells. In conclusion, this review discusses progress in human liver immunology modeling and highlights limitations and numerous untapped opportunities. These include the potential to model in vitro autoimmunity and more complex myeloid inflammatory responses, incorporating contributions from embryonic tissue and bone marrow. Additionally, future in vitro models may include hard-to-culture populations such as neutrophils.","PeriodicalId":9950,"journal":{"name":"Cellular &Molecular Immunology","volume":"22 10","pages":"1226-1236"},"PeriodicalIF":19.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41423-025-01312-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552479","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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