CELL RESEARCH
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2025
·
IF 25.9
Qin Rui,Zhang Yong,Shi Jiawei,Wu Peng,An Chenyi,Li Zhenhai,Liu Nuo,Wan Ziyan,Hua Ting,Li Xiaolong,Lou Jizhong,Yin Weiwei,Chen Wei
Naturally evolved T-cell receptors (TCRs) exhibit remarkably high specificity in discriminating non-self antigens from self-antigens under dynamic biomechanical modulation. In contrast, engineered high-affinity TCRs often lose this specificity, leading to cross-reactivity with self-antigens and off-target toxicity. The underlying mechanism for this difference remains unclear. Our study reveals that natural TCRs exploit mechanical force to form optimal catch bonds with their cognate antigens. This process relies on a mechanically flexible TCR–pMHC binding interface, which enables force-enhanced CD8 coreceptor binding to MHC-α 1 α 2 domains through sequential conformational changes induced by force in both the MHC and CD8. Conversely, engineered high-affinity TCRs create rigid, tightly bound interfaces with cognate pMHCs of their parental TCRs. This rigidity prevents the force-induced conformational changes necessary for optimal catch-bond formation. Paradoxically, these high-affinity TCRs can form moderate catch bonds with non-stimulatory pMHCs of their parental TCRs, leading to off-target cross-reactivity and reduced specificity. We have also developed comprehensive force-dependent TCR–pMHC kinetics-function maps capable of distinguishing functional and non-functional TCR–pMHC pairs and identifying toxic, cross-reactive TCRs. These findings elucidate the mechano-chemical basis of the specificity of natural TCRs and highlight the critical role of CD8 in targeting cognate antigens. This work provides valuable insights for engineering TCRs with enhanced specificity and potency against non-self antigens, particularly for applications in cancer immunotherapy and infectious disease treatment, while minimizing the risk of self-antigen cross-reactivity.
研究领域:
免疫学
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细胞生物学
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生物力学
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DOI
PubMed
高影响因子
MOLECULAR CELL
·
2024
·
IF 14.5
Zhenxi Zhang,Yanting Yang,Yang Chen,Jingyu Su,Wenjing Du
The functional integrity of CD8 + T cells is closely linked to metabolic reprogramming; therefore, understanding the metabolic basis of CD8 + T cell activation and antitumor immunity could provide insights into tumor immunotherapy. Here, we report that ME2 is critical for mouse CD8 + T cell activation and immune response against malignancy. ME2 deficiency suppresses CD8 + T cell activation and anti-tumor immune response in vitro and in vivo . Mechanistically, ME2 depletion blocks the TCA cycle flux, leading to the accumulation of fumarate. Fumarate directly binds to DAPK1 and inhibits its activity by competing with ATP for binding. Notably, pharmacological inhibition of DAPK1 abolishes the anti-tumor function conferred by ME2 to CD8 + T cells. Collectively, these findings demonstrate a role for ME2 in the regulation of CD8 + T cell metabolism and effector functions as well as an unexpected function for fumarate as a metabolic signal in the inhibition of DAPK1.
研究领域:
免疫学
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肿瘤学
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代谢生物学
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产品关联
DOI
PubMed
高影响因子
Mucosal Immunology
·
2024
·
IF 7.9
Xixi Huang,Tingxuan Yin,Min Yu,Guohua Zhu,Xianyang Hu,Hailin Yu,Weijie Zhao,Jiajia Chen,Jiangyuan Du,Qingyu Wu,Wei Zhang,Lu Liu,Meirong Du
Decidual CD8 + T (dCD8 + T) cells are pivotal in the maintenance of the delicate balance between immune tolerance towards the fetus and immune resistance against pathogens. The endometrium and decidua represent uterine environments before and during pregnancy, respectively, and the composition and phenotypic alterations of uterine CD8 + T cells in these tissues remain unclear. Using flow cytometry and analysis of transcriptome profiles, we demonstrated that human dCD8 + T and endometrial CD8 + T (eCD8 + T) cells exhibited similar T cell differentiation statuses and phenotypes of tissue infiltrating or residency, compared to peripheral CD8 + T (pCD8 + T) cells. However, dCD8 + T cells showed decreased expression of coinhibitory (PD-1), chemotaxis (CXCR3), and tissue-resident (CD69 and CD103) markers and increased granzyme B and granulysin expression compared to eCD8 + T cells. In vitro, cytotoxicity assays demonstrated greater effector functions in dCD8 + T cells than in eCD8 + T cells. Further in vitro and in vivo chemotaxis assays confirmed the recruitment of non-resident effector memory T cell subsets to the pregnant decidua, contributing to the dCD8 + T cell-mediated anti-infection mechanism at the maternal-fetal interface. This work demonstrated dCD8 + T cells replenished from the circulation retained their cytotoxic capacity, which may serve as an enhanced defense mechanism against infection during pregnancy.
研究领域:
免疫学
·
生殖生物学
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妊娠免疫学
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DOI
PubMed
高影响因子
Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-13
·
IF 7
Jiang Xiaoxiao,Fan Zhijin,Zhang Zhenzhen,Zeng Fanchu,Sun Tong,Li Yuchen,Huang Guojia,Nie Liming
Tumor cells balance ATP production and carbon skeleton synthesis by flexibly altering catabolic pathways to sustain their significant growth advantage. Uncouplers have shown potential for tumor suppression by converting chemical energy from catabolism into heat. However, their use may be limited due to indiscriminate metabolic interference in both tumor and normal cells, as well as the uncertainty surrounding their effects on the immune microenvironment. Herein, we found that low-dose uncoupler BAM15 promoted AMPK, AKT signaling, and the TCA cycle without increasing cell proliferation or inducing cell death in vitro, suggesting an increase in futile cycling. Intratumoral injection of 50 ng/mL BAM15 accelerated catabolic processes while inhibiting anabolic pathways, resulting in a metabolomic reshaping with increased levels of linoleic acid, C5DC, and others. These changes were shown to enhance tumor-killing effects by T cells. To reduce side effects on normal tissues and improve tumor retention, BAM15 was targeted for delivery by loading it into TCVs. This TCV-BAM15 treatment significantly increased CD8+ T cell counts and granzyme B levels. Our findings highlight a previously unrecognized therapeutic effect and signaling mechanism of low-dose BAM15 treatment in tumors. We propose that this novel strategy holds promise as a tumor immunity therapy with fewer adverse effects compared to free uncoupling drugs at high concentrations.
研究领域:
肿瘤学
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免疫学
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生物化学
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药理学
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产品关联
DOI
PubMed
高影响因子
HELICOBACTER
·
2023
·
IF 4.4
Zelin Zhang,Xingchi Chen,Bin Li,Tingting Xia,Xiaobin Wu,Chao Wu
Background Urease subunit B (UreB), a conserved and key virulence factor of Helicobacter pylori ( H. pylori ), can induce the host CD4 + T cell immune responses to provide protection, but less is known regarding CD8 + T cell responses. The characteristics of H. pylori -specific CD8 + T cell responses and the mechanism underlying antigen processing and presentation pathways remain unclear. This study was focus on protective antigen recombinant UreB (rUreb) to detect specific CD8 + T cell responses in vitro and elucidate the mechanism of UreB antigen processing and presentation. Methods The peripheral blood mononuclear cells (PBMCs) collected from H. pylori -infected individuals were stimulated with rUreB in vitro to detect specific CD8 + T cell responses after co-culture with rUreB-pulsed autologous hMDCs. Through blocking assay, we investigated the potential pathway of UreB antigen processing and presentation via the cytosolic pathway or vacuolar pathway. The cytokines production of UreB specific CD8 + T cell were evaluated as well. Results We demonstrated UreB can induce specific CD8 + T cell immune responses in H. pylori infected individuals. Importantly, we characterized that UreB were mainly processed by proteasome instead of lysosomal proteases and presented through cytosolic pathway of cross-presentation, which requires endoplasmic reticulum–Golgi transport and newly synthesized MHC-I molecules, to induce functional-specific CD8 + T cell (IFN-γ + TNF-α + Grz A+ Grz B+) responses. Conclusions These results suggest that H. pylori UreB induces specific CD8 + T cell responses through cytosolic pathway of cross-presentation in infected individuals.
研究领域:
免疫学
·
病原生物学
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医学
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2019
·
IF 4.511
Yongli Fan,Yongkui Li,Jian Zhang,Xiuli Ding,Jinyuan Cui,Guobin Wang,Zheng Wang,Lin Wang
Alginate, an FDA-approved natural biomaterial usually used as a therapeutic adjuvant, drug carrier, and biological scaffold, reportedly assists the immune system to activate cytotoxic T cells in antitumor assays. In this study, we investigated the direct effect of alginate on cytotoxic T cell function. By incubating sorted cytotoxic CD8+ T cells with alginate, we found that this material facilitated the antitumor cytotoxic activities of T cells. Alginate incubation significantly promoted memory properties of CD8+ T cells and elevated the proportion of CD62L+CD44+ central memory T cell (TCM), a less differentiated T cell subset with high immune activity. Mechanistically, alginate reduced reactive oxide species in CD8+ T cells by increasing intracellular glutathione generation, which was critical for conferring T cells with memory properties. Further, we found that guluronic acid, a constituent component (G unit) of alginate, is responsible for inducing glutathione and promoting TCM. Collectively, we reported new biological activities of alginate on scavenging reactive oxide species and regulating the function of cytotoxic T cells, which suggests that alginate and guluronic acid may be used for improving cytotoxic T cell functions in immunotherapy.
研究领域:
免疫学
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癌症生物学
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生物医学工程
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DOI
PubMed
高影响因子
Cell Metabolism
·
2023
·
IF 29
Jie Cheng,Jinxin Yan,Ying Liu,Jiangzhou Shi,Haoyu Wang,Hanyang Zhou,Yinglin Zhou,Tongcun Zhang,Lina Zhao,Xianbin Meng,Haipeng Gong,Xinxiang Zhang,Haichuan Zhu,Peng Jiang
Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8 + T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8 + T cells, resulting in suppressed CD8 + T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8 + T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.
研究领域:
肿瘤学
·
免疫学
·
代谢学
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产品关联
DOI
PubMed
高影响因子
CELL
·
2024
·
IF 45.5
Jinjia Zhang,Junhong Li,Yongqiang Hou,Yao Lin,Hao Zhao,Yiran Shi,Kaiyun Chen,Cheng Nian,Jiayu Tang,Lei Pan,Yunzhi Xing,Huan Gao,Bingying Yang,Zengfang Song,Yao Cheng,Yue Liu,Min Sun,Yueyue Linghu,Jiaxin Li,Haitao Huang,Zhangjian Lai,Zhien Zhou,Zifeng Li,Xiufeng Sun,Qinghua Chen,Dongxue Su,Wengang Li,Zhihai Peng,Pingguo Liu,Wei Chen,Hongling Huang,Yixin Chen,Bailong Xiao,Lilin Ye,Lanfen Chen,Dawang Zhou
Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8 + T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8 + T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8 + T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8 + T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8 + T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8 + T cell exhaustion and could be targeted to potentiate cancer immunotherapy.
研究领域:
免疫学
·
癌症生物学
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细胞生物学
·
转录调控
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产品关联
DOI
PubMed
高影响因子
Arthritis & Rheumatology
·
2025
·
IF 10.9
Jin-Fen Ma,Ting Xu,Hao-Xian Zhu,Xiao-Min Chen,Liang Li,Zhi-Bin Zhao,Liwei Lu,Yang Li,Zhe-Xiong Lian,Cai-Yue Gao
Objective Activated T cells play a pivotal pathogenic role in the progression of Sjögren disease (SjD); however, there are currently no targeted therapies specifically designed to address them. This study aims to identify pathogenic CD8 + T cells in SjD and develop targeted therapeutic strategies. Methods Il12b-/-Il2ra-/- mice, a murine model for overlapping primary biliary cholangitis and SjD, were employed in this study. Pathogenic CD8 + T cells were identified through single-cell RNA sequencing and flow cytometry analyses of samples from both patients with SjD and relevant murine models. Shared T cell receptor analysis was conducted to trace the potential precursors of pathogenic CD8 + T cells. The efficacy of PD-1-targeted chimeric antigen receptor (CAR)–T cell therapy was evaluated through the assessment of salivary gland secretory function, immunologic profiles, and histopathological changes in the murine model. Results We identified PD-1 as a comprehensive marker of clonally expanded and activated pathogenic CD8 + T cells in the salivary glands and peripheral tissues. Flow cytometry further confirmed the activation phenotype and cytotoxicity of PD-1 + CD8 + T cells in the salivary glands of patients with SjD. Notably, the number of PD-1 + CD8 + T cells in the labial glands positively correlated with disease activity in patients with SjD. These findings highlight the therapeutic potential of depleting PD-1 + CD8 + T cells in SjD. Furthermore, PD-1-targeted CAR-T cell therapy significantly alleviated SjD symptoms in a murine model. Conclusion We identified the pathogenic role of PD-1 + CD8 + T cells in both patients with SjD and a murine model and demonstrated the efficacy of PD-1-targeted CAR-T cell therapy in SjD model mice. Our findings suggest a promising avenue for developing clinical therapeutic strategies for patients with SjD.
研究领域:
免疫学
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医学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2025
·Vol. 10
·期 1
·1-17
·
IF 52.7
Tang Yu,Luo Zhiyuan,Ma Zhanni,Han Lingling,Zhou Yurong,Liang Tianci,Yang Kangsen,Zhao Lei,Chen Xiaoyuan,Zhang Pengfei
The variety and functionality of current clinical vaccine adjuvants remain limited. Conventional aluminum-based adjuvants predominantly induce Th2-biased humoral immunity but exhibit a limited capacity to elicit Th1-mediated cellular immune responses, particularly tumor antigen-specific cytotoxic CD8 + T lymphocytes (CTLs), which are essential for effective cancer vaccine performance. Inspired by natural biomolecular condensates, we developed a versatile noncovalent protein self-assembly strategy distinct from traditional approaches requiring structural domain modifications or bifunctional crosslinkers. Our methodology employs amphiphilic molecules (sodium myristate/SMA and sodium dodecyl thiolate/SDT) as molecular bridges to mediate protein‒protein interactions through hydrophobic forces and disulfide bond formation. This process generates nanoscale protein condensate (PCD) vaccines with exceptional stability. As a novel adjuvant system, these synthetic condensates significantly enhance antigen cross-presentation by optimizing key parameters: antigen loading capacity, lymph node targeting, cytosolic delivery, and lysosomal escape. Consequently, they induce robust antigen-specific CTL responses and humoral immunity, demonstrating potent antitumor efficacy. Importantly, we found that the synthetic protein condensate (PCD) alone can act as a nanoadjuvant. By increasing mitochondrial membrane permeability, PCD induces mitochondrial DNA leakage into the cytosol, activating the cGAS‒STING pathway and promoting DC maturation. This safe and scalable platform eliminates the need for complex covalent modifications or genetic engineering, and it facilitates the design of diverse modular antigens, including neoantigens and viral antigens. Given its straightforward manufacturing process and superior immunogenicity, this synthetic PCD vaccine adjuvant has significant potential for clinical application and translation.
研究领域:
免疫学
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肿瘤学
·
纳米医学
·
分子生物学
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转化医学
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疫苗学
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产品关联
DOI
PubMed
高影响因子
MEDICAL SCIENCE MONITOR
·
2019
·
IF 1.98
Liang Chen,Hanfei Huang,Weixin Zhang,Feifan Ding,Zhenlei Fan,Zhong Zeng
Background CD8 + cytotoxic T lymphocytes (CTLs) have been proved to exert crucial roles in immunological rejection. Exosomes (EXOs) secreted by CD4 + CD25 + regulatory T (Treg) cells is believed to be deeply involved in immune regulation. Nevertheless, whether immunomodulatory effect of CD4 + CD25 + Treg cells on CD8 + CTL depends on EXOs remains unknown and needs to be explored. Material/Methods We purified CD4 + CD25 + Treg cells followed by in vitro amplification. EXOs in culture supernatants of Treg cells was separated and identified. The effect of CD4 + CD25 + Treg cells and CD4 + CD25 + Treg cells-derived EXOs on CD8 + CTL viability, proliferation, cell cycle mRNA, intracellular cytokines, and protein expression were investigated. Results We successfully obtained EXOs from CD4 + CD25 + Treg cells. The inhibition effect of EXOs on CD8 + CTL was concentration-dependent. In addition, the inhibition effect of CD4 + CD25 + Treg cells could be reversed by GW4869, an EXOs inhibitor. The inhibition effect was associated with the regulation of IFN-γ and perforin. Our in vivo experiments proved that natural CD4 + CD25 + Treg cells-released EXOs can prolong liver allograft survival. Conclusions CD4 + CD25 + Treg cells-derived EXOs could become an alternative tool for manipulating the immune system to discover novel underlying immunomodulatory mechanisms.
研究领域:
免疫学
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移植医学
·
细胞生物学
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DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Yu Han,Kai Zhang,Ning Xin,Xintao Gao,Guohua Ma,Jingtong An,Yantao Li
Despite recent advancements in lipid nanoparticles (LNPs)-based messenger RNA (mRNA) delivery, significant challenges persist in the structural optimization and functional modulation of their components for cancer immunotherapy, particularly regarding inadequate organ-specific targeting, and insufficient immune activation. Notably, metal ions have demonstrated emerging immunomodulatory potential, yet their coordinated self-assembly within LNPs as adjuvants to enhance the immunotherapeutic efficacy remains largely unexplored. To address these limitations, we combine newly designed imidazole-based LNPs with functional metal ions (Zn 2+ ) to develop novel Zn-coordinated LNP-based mRNA vaccines. A total of 48 imidazole-based ionizable lipids were designed and synthesized, among which C2–13 LNPs emerged as the top-performing formulation in terms of transfection efficiency. By innovatively incorporating Zn 2+ into C2–13 LNPs via coordination interaction, we further developed the novel metal-coordinated mRNA delivery systems, referred to as Zn-C2–13 LNPs. Compared to their non-metal counterparts, Zn-C2–13 LNPs exhibited markedly improved transfection efficiency and antigen presentation in vitro . Impressively, the synergistic effect of the optimized LNP formulation and Zn 2+ in the Zn-C2–13/mOVA systems (Zn-C2–13 LNPs loading ovalbumin mRNA) resulted in superior spleen-selective expression and immune response, significantly boosting the efficacy of cancer immunotherapy in the B16F10 ovalbumin-expressing (B16F10-OVA) melanoma tumor model. Collectively, this novel metal-coordinated LNPs improve specific organ targeting and immune responses, presenting a promising strategy to advance mRNA vaccine-based cancer immunotherapy.
研究领域:
免疫学
·
肿瘤学
·
纳米医学
·
分子生物学
·
转化医学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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