Nature Communications
·
2026
·
IF 18.1
Zhao Lei,Gao Zhongqiang,Yuan Ze,Yang Xiaodie,Li Duxin,Ren Qian,Yu Yunli,Pan Jie,Zheng Yiran,Zhang Xinyun
Inducing antigen-specific regulatory T (T reg ) cells is a promising strategy for treating autoimmune diseases (AID). Here, we present dendritic cells-CD4⁺ T cells (DC-CD4) bispecific tolerogenic nanovesicles (NV) co-loaded with an antigenic peptide and rapamycin. We show that these NVs bring DCs and CD4⁺ T cells into close spatial proximity through CTLA4-CD80/86 and anti-CD4 (aCD4)-CD4 interactions, thereby promoting antigen-specific T reg cell generation. In a collagen-induced arthritis mouse model, the bispecific NVs display enhanced lymph node (LN) tropism and increase antigen-specific T reg cells in LNs and spleen, when administered in both therapeutic and prophylactic settings, resulting in robust efficacy against CIA. Furthermore, arthritogenic cell transfer and adoptive transfer of T reg cells into T reg -ablated mice confirm the pivotal role of bispecific NV-induced antigen-specific T reg cells in mediating the anti-inflammatory efficacy. Collectively, our data support DC-CD4 bispecific tolerogenic NVs as a platform to induce antigen-specific T reg cells for precise immune tolerance in AIDs.
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PubMed
高影响因子
Journal of Innate Immunity
·
2020
·Vol. 13
·期 1
·38-48
·
IF 4.932
Wang Tianyue,Zhou Qianlan,Shang Yunxiao
Children exposed to common aeroallergens may develop asthma that progresses into adulthood. Inflammation regulated by T helper 2 (Th2) cells, a specific subpopulation of CD4+ T lymphocytes, is involved in asthmatic injury. Herein, our microarray data indicated that microRNA-451a-5p (miRNA-451a) expression decreased by 4.6-fold and ETS proto-oncogene 1 (ETS1) increased by 2.2-fold in the peripheral blood lymphocytes isolated from asthmatic children (n = 4) as compared to control individuals (n = 4). The negative correlation between miRNA-451a and ETS1 was further validated in 40 CD4+ T cell samples (10 healthy vs. 30 asthmatic samples). In vitro, naïve CD4+ T cells isolated from control individuals were cultured under Th2 cell polarizing condition. miRNA-451a expression decreased while ETS1 increased in CD4+ T cells in the setting of Th2 cell polarization. Moreover, miRNA-451a knockdown enhanced Th2 cell polarization – cells positive for both GATA3 (GATA binding protein 3, a Th2-transcription factor) and CD4 increased, and the generation of Th2 cell cytokines, interleukin (IL)5 and IL13, increased. In contrast, miRNA-451a overexpression inhibited Th2 cell differentiation. Interestingly, dual-Luciferase assay proved ETS1 as a novel target of miRNA-451a. Moreover, enforced expression of ETS1 partially restored miRNA-451a-induced inhibition of IL5 and IL13, and increased the GATA3+CD4+ cell population. Collectively, our work demonstrates that downregulation of miRNA-451a upregulates ETS1 expression in CD4+ T cells, which may contribute to Th2 cell differentiation in pediatric asthma
研究领域:
免疫学
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分子生物学
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儿科
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PubMed
高影响因子
Journal of Magnesium and Alloys
·
2025
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IF 13.8
Shubo Liu,Qinghua Chen,Yaowen Xu,Haidong Yu,Jue Cao,Zichu Ding,Weixin Zheng,Keyu Chen,Yuexin Zhao,Yan Shi,Shaoxiong Min,Ben Wang,Jie Shen,Bin Chen
The clinical challenges of bone defect repair have driven the exploration of novel biomaterials with immunomodulatory and osteogenic functionalities. While previous studies predominantly focused on macrophages in the osteoimmune microenvironment, the regulatory mechanisms of T cells, particularly "conductor" CD4 + T cells, remain poorly understood. This study investigated the effects of magnesium ions (Mg 2+ ) on CD4 + T cell polarization and their mediated bone regeneration using Mg 2+ -functionalized composite materials. Results demonstrated that suitable Mg 2+ concentration range significantly enhanced CD4 + T cell activation and proliferation, promoting polarization toward Th1 and Treg subtypes, thereby establishing a pro-inflammatory and anti-inflammatory synergistic immune microenvironment. Conditioned medium experiments further confirmed that cytokines secreted from CD4 + T cells synergized with Mg 2+ to augment alkaline phosphatase activity and calcium deposition in bone marrow mesenchymal stem cells (MSCs), while mitigating the inhibitory effects of high Mg 2+ concentrations on osteogenesis. Then, nano-magnesium oxide-doped polycaprolactone scaffolds (Mg-PCL) and T cell activator-crosslinked magnesium-alginate hydrogels (T-Mg-Gel) were engineered to control the release of Mg 2+ . In vivo evaluations revealed that 1%Mg-PCL scaffolds facilitated membranous ossification in cranial defects via sustained Mg 2+ release, whereas T-Mg-Gel accelerated bone regeneration by suppressing early-stage inflammation and promoting long-term Treg cell regulation. This study revealed the pivotal role of CD4 + T cells in osteoimmunology and provides a novel strategy for designing intelligent bone repair materials with dual immunomodulatory and osteogenic capabilities.
研究领域:
生物材料
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组织工程
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免疫学
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再生医学
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生物医学工程
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细胞生物学
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生物化学
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DOI
高影响因子
Journal of Molecular Cell Biology
·
2022
·Vol. 14
·期 12
·
IF 8.185
Han Yuheng,Ouyang Xinxing,Chen Yao,Lai Shujing,Sun Hongxiang,Wu Ningbo,Ruan Chun,Lu Limin,Su Bing
It is well documented that the neonatal thymus-derived (neonatal-TD) regulatory T cells (Treg) are essential to prevent lethal autoimmune diseases and allergies, and neonatal and adult thymus possesses distinct output potentials for naïve T cells, including Treg. However, the molecular features and detailed functional differences between neonatal-TD and adult thymus-derived (adult-TD) T cells in terms of their ability to maintain immune homeostasis during long-term environmental influences are still largely unknown, partially due to the lack of appropriate animal models to precisely trace these cells at specific time points. In this study, neonatal-TD and adult-TD CD4+ T cells from the spleen and Peyer's patches were traced for 9 weeks by a T cell origin-time tracing mouse model and analysed by single-cell RNA sequencing. More Treg but fewer naïve T cells were found in neonatal-TD CD4+ T cells from both tissues than those from adult-TD counterparts. Interestingly, the neonatal-TD Treg in both the spleen and Peyer's patches exhibited augmented expression of Foxp3, Gata3, Ctla4, Icos, Il2ra, Tgfb1, and Nrp1, as well as enriched Gene Ontology terms like T cell activation and tolerance induction, indicating an enhanced immunosuppressive function. These results were further confirmed by flow cytometry analysis and in vitro immune suppression assays. Flow cytometry also revealed a significantly higher proportion of neonatal-TD Treg in total Treg than that of adult-TD counterparts, suggesting the longer lifespan of neonatal-TD Treg. To investigate the intrinsic features of neonatal-TD and adult-TD CD4+ T cells, a shortened tracing time was performed. Surprisingly, the neonatal-TD and adult-TD CD4+ T cells had similar proportions of Treg and did not exhibit significant differences in Foxp3, Gata3, Ctla4, Icos, Il2ra, and Tgfb1 expression levels after tracing for 12 days. On the other hand, neonatal-TD Treg present an increased Nrp1 expression level compared with adult-TD counterparts, indicating the enhanced stability. Together, our work reveals that the neonatal-TD Treg are more immunosuppressive, which is likely shaped primarily by environmental factors.
研究领域:
免疫学
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分子生物学
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基因组学
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PubMed
高影响因子
Heliyon
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2023
·
IF 4
Ran Tu,Cheng Zhou,Wenfeng Huang,Zhengping Feng,Qiufang Zhao,Xiaofei Shi,Langjun Cui,Keke Chen
Rationale and objectives Fuzi, the dried root of Aconitum carmichaelii Debx, is one of the widely used traditional Chinese medicines. Fuzi polysaccharides are considered the most bioactive compounds with immunomodulatory functions, however, the mechanisms have not been evaluated. This study aims to systematically investigate the effects of Fuzi polysaccharides on the gut microbiota and immune function using a mouse model immunosuppressed with cyclophosphamide. Methods The short-chain fatty acid levels in cecal contents were measured by gas chromatography-mass spectrometry. The gut microbiota 16S rRNA gene were sequenced by next generation sequencing. The mRNA expression levels of NF-κB, IL-6, TNF-α, iNOS and COX-2 were measured using quantitative real-time polymerase chain reaction. The protein expression of occludin and zonula occludens-1 were analyzed by Western blot. The white blood cells were counted using automated hematology analyzer, and CD4 + FOXP3 + /CD4 + ratio was measured by flow cytometry. Results and Conclusions Fuzi polysaccharides had the function of elevating the concentration of acetic acid, propionic acid, isobutyric acid, and n-butyric acid in the cecum. Meanwhile, Fuzi polysaccharides could decrease the relative abundance of Helicobacter , Anaerotruncus , Faecalibacterium , Lachnospira , Erysipelotrichaceae _UCG-003, Mucispirillum , and Mycoplasma , and increase the relative abundance of Rhodospirillales , Ruminococcaceae _UCG-013, Mollicutes _RF39, Ruminococcus _1, Christensenellaceae _R-7_group, and Muribaculaceae in the gut. Furthermore, Fuzi polysaccharides exhibited the function of increasing spleen and thymus indices and number of white blood cells and lymphocytes. Fuzi polysaccharides could reverse the decreased mRNA expression of NF-кB, IL-6, and iNOS, differentiation of CD4 + FOXP3 + regulatory T cells as well as protein expression of occludin and zonula occludens-1 induced by cyclophosphamide. In addition, the mRNA and protein expression of cytokines were significantly correlated with the abundance of gut microbiota under Fuzi polysaccharides treatment. Collectively, the above results demonstrated that Fuzi polysaccharides could regulate inflammatory cytokines and gut microbiota composition of immunosuppressive mice to improve immunity, thereby shedding light on revealing the molecular mechanism of polysaccharides of traditional Chinese medicines in the future.
研究领域:
免疫学
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微生物学
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药理学
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中药学
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DOI
PubMed
高影响因子
Clinical and Vaccine Immunology
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2005
·Vol. 12
·期 11
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IF 0
Yongjun Jiang,Hong Shang,Zining Zhang,Yingying Diao,Di Dai,Wenqing Geng,Min Zhang,Xiaoxu Han,Yanan Wang,Jing Liu
Natural killer (NK) cells, natural killer T (NKT) cells, and T lymphocytes were analyzed by using a flow cytometer in 225 human immunodeficiency virus (HIV)-positive individuals infected through the past sale of blood and plasma without receiving antiretroviral therapy in the People’s Republic of China. According to CD4 T-cell counts these HIV-infected adults were stratified into three groups: long-term slow progressors, HIV-infected subjects, and AIDS patients. NK cell counts in long-term slow progressors were higher compared to HIV infection and AIDS patients (P < 0.05) and lower compared to normal controls (P < 0.05), whereas NKT cell counts in slow progressors and the HIV infection group were not different from those of normal controls. NK cell counts in HIV-seropositive subjects were positively correlated with CD4 T-cell counts (P < 0.05), and NKT cell counts were positively correlated with CD4 T-cell and CD8 T-cell counts (P < 0.05). The CD8 T-cell counts were higher in slow progressors compared to those with HIV infection, AIDS patients, and normal controls. These results indicated that HIV infection causes alterations of NK cells and T cells in slow progressors, HIV-infected subjects, and AIDS patient groups, but no difference was found in NKT cell counts and percentages in slow progressors and the HIV-infected group compared to normal controls.
研究领域:
免疫学
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病毒学
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DOI
PubMed
MOLECULAR IMMUNOLOGY
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2023
·
IF 3.6
Wei Zhong,Leheng Feng,Wei Tian,Hongbo Qu,Haibo Xu,Ke Ning,Li Liu,Wei Liu,Xiaowei Gong,Hong Chen
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease . This study aimed to investigate the role of SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) in the Th17 and Th17.1 differentiation and Treg/Th17 imbalance, which are major factors contributing to the pathogenesis of SLE. SLE patients and healthy individuals were recruited to detect the SMURF1 levels in naïve CD4 + cells from peripheral blood. Purified and expanded naïve CD4 + T cells were employed to evaluate the effects of SMURF1 on Th17 and Th17.1 polarization in vitro. MRL/lpr lupus model was employed to explore the disease phenotype as well as Treg/Th17 balance in vivo. The results showed that SMURF1 was down-regulated in naïve CD4 + T cells in peripheral blood of patients with SLE and in spleen of MRL/lpr mice. SMURF1 overexpression suppressed the polarization of naïve CD4 + T cells toward Th17 and Th17.1 phenotype and down-regulated the expression of retinoid-related orphan receptor-gammat (RORγt). Subsequently, SMURF1 down-regulation aggravated the disease phenotype, inflammation, and the Treg/Th17 imbalance in MRL/lpr mice. Furthermore, we found that SMURF overexpression promoted the ubiquitination and decreases the stability of RORγt. In conclusion, SMURF1 inhibited the polarization of Th17 and Th17.1 cells and improved the Treg/Th17 imbalance in SLE, which was mediated as least partly by the ubiquitination of RORγt.
研究领域:
免疫学
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自身免疫性疾病
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Neuroscience
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2022
·
IF 5.152
Yan-Lin Chen,Lan Bai,Dilirebati Dilimulati,Shuai Shao,Che Qiu,Ting Liu,Shuo Xu,Xue-Bing Bai,Lin-Juan Du,Lu-Jun Zhou,Wen-Zhen Lin,Xiao-Qian Meng,Yi-Chao Jin,Yan Liu,Xiao-Hua Zhang,Sheng-Zhong Duan,Feng Jia
Although epidemiological studies suggest that periodontitis is tightly associated with ischemic stroke, its impact on ischemic stroke and the underlysing mechanisms are poorly understood. Recent studies have shown that alteration in gut microbiota composition influences the outcomes of ischemic stroke. In the state of periodontitis, many oral pathogenic bacteria in the saliva are swallowed and transmitted to the gut. However, the role of periodontitis microbiota in the pathogenesis and progression of ischemic stroke is unclear. Therefore, we hypothesized that the periodontitis salivary microbiota influences the gut immune system and aggravates ischemic stroke. Mice receiving gavage of periodontitis salivary microbiota showed significantly worse stroke outcomes. And these mice also manifested more severe neuroinflammation, with higher infiltration of inflammatory cells and expression of inflammatory cytokines in the ischemic brain. More accumulation of Th17 cells and IL-17 + γδ T cells were observed in the ileum. And in Kaede transgenic mice after photoconversion. Migration of CD4 + T cells and γδ T cells from the ileum to the brain was observed after ischemic stroke in photoconverted Kaede transgenic mice. Furthermore, the worse stroke outcome was abolished in the IL-17A knockout mice. These findings suggest that periodontitis salivary microbiota increased IL-17A-producing immune cells in the gut, likely promoted the migration of these cells from the gut to the brain, and subsequently provoked neuroinflammation after ischemic stroke. These findings have revealed the role of periodontitis in ischemic stroke through the gut and provided new insights into the worse outcome of ischemic stroke coexisting with periodontitis in clinical trials.
研究领域:
神经科学
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免疫学
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微生物学
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病理学
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PubMed
高影响因子
Small
·
2024
·
IF 13
Jiabao Dong,Xupeng Chai,Yucheng Xue,Shiyun Shen,Zhuo Chen,Zetao Wang,Eloy Yinwang,Shengdong Wang,Liang Chen,Fengfeng Wu,Hengyuan Li,Zehao Chen,Jianbin Xu,Zhaoming Ye,Xiongfeng Li,Qian Lu
Adoptive cellular therapy is a promising strategy for cancer treatment. However, the effectiveness of this therapy is limited by its intricate and immunosuppressive tumor microenvironment. In this study, a targeted therapeutic strategy for macrophage loading of drugs is presented to enhance anti-tumor efficacy of macrophages. K7M2-target peptide (KTP) is used to modify macrophages to enhance their affinity for tumors. Pexidartinib-loaded ZIF-8 nanoparticles (P@ZIF-8) are loaded into macrophages to synergistically alleviate the immunosuppressive tumor microenvironment synergistically. Thus, the M1 macrophages decorated with KTP carried P@ZIF-8 and are named P@ZIF/M1-KTP. The tumor volumes in the P@ZIF/M1-KTP group are significantly smaller than those in the other groups, indicating that P@ZIF/M1-KTP exhibited enhanced anti-tumor efficacy. Mechanistically, an increased ratio of CD4+ T cells and a decreased ratio of MDSCs in the tumor tissues after treatment with P@ZIF/M1-KTP indicated that it can alleviate the immunosuppressive tumor microenvironment. RNA-seq further confirms the enhanced immune cell function. Consequently, P@ZIF/M1-KTP has great potential as a novel adoptive cellular therapeutic strategy for tumors.
研究领域:
癌症生物学
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药学
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免疫治疗
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DOI
PubMed
高影响因子
ACS Omega
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2022
·
IF 4.132
Yanju Gao,Bo Zhou,Han Zhang,Lin Chen,Xiaohong Wang,Hongbing Chen,Lin Zhou
Background: Ulcerative colitis (UC) is a chronic disease of the intestinal tract in which excessive activation of inflammatory response is correlated. l-Ergothioneine (EGT) widely existing in mushrooms has various physiological activities. In this study, the protective effects of EGT on dextran sulfate sodium (DSS)-induced colitis mice were investigated. Results: It was observed that EGT administration, especially at the high dose level, prevented the body weight loss, the colon shortening, and the increase in disease activity index and spleen index caused by DSS. Moreover, EGT supplementation attenuated DSS-induced gut barrier damage by enhancing the expression of tight-junction protein and recovering the loss of gut mucus layer. Furthermore, EGT considerably decreased the colonic myeloperoxidase (MPO) activity induced by DSS, but no significant differences were observed in the concentrations of IL-6 and TNF-α in colon tissues. Additionally, EGT downregulated the populations of CD4+ T cells and macrophages, indicating that EGT stabilized the immune response caused by DSS. Conclusion: Together these results suggest that EGT can alleviate DSS-induced colitis and provide important insights concerning the potential anticolitis activity of such food products.
研究领域:
免疫学
·
胃肠病学
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药理学
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产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
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2024
·
IF 5.4
Yuting Hou,Zhe Wang,Zhen Chen,Lan Shuai,Yifei Pei,Binbin Sun,Yuxin Jiang,Hongsheng Wang
It is difficult to obtain specific tumor antigens, which is one of the main obstacles in the development of tumor vaccines. The vaccines containing multivalent antigens are thought to be more effective in antitumor therapy. In this study, a mRNA encoding three neoantigens of melanoma were prepared and encapsulated into the mannosylated chitosan-modified ethosomes (EthsMC) to obtain a multivalent mRNA vaccine (MmRV) for transcutaneous immunization (TCI). MmRV can effectively induce maturation of dendritic cells, with a better performance than mRNA of a single neoantigen. TCI patches (TCIPs) loading MmRV or siRNA against PDL1 (siPDL1) were prepared and applied to the skin of melanoma-bearing mice. The results showed that TCIPs significantly increase the levels of TNF-α, IFN-γ, and IL-12 in both plasma and tumor tissues, inhibit tumor growth, as well as promote infiltration of CD4+ and CD8+ T cells in the tumor tissues. Furthermore, the combination of MmRV and siPDL1 showed much better antitumor effects than either monotherapy, suggesting a synergistic effect between the vaccine and PDL1 blocker. In addition, the treatment with the TCIPs did not cause damage to the skin, blood, and vital organs of the mice, showing good biosafety. To the best of our knowledge, this work is the first to construct a noninvasive TCI system containing MmRV and siPDL1, providing a convenient and promising approach for tumor treatment.
研究领域:
肿瘤学
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免疫学
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药学
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生物技术
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DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2024
·
IF 4
Wang Liping,Liang Aihua,Huang Jukai
Introduction: Diabetic nephropathy (DN) presents a significant therapeutic challenge, compounded by complex pathophysiological mechanisms. Recent studies suggest Exendin-4 (Ex-4) as a potential ameliorative agent for DN, albeit with unclear mechanisms. This research investigates the effects and underlying mechanisms of Ex-4-enriched exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs) on DN, focusing on their renoprotective properties and interactions with gut microbiota.Method: Exosomes from hUCMSCs (hUCMSCs-Exo) were loaded with Ex-4 via electroporation. A streptozotocin (STZ) -induced DN mouse model was employed to assess the therapeutic impact of these engineered exosomes. The study further explored immune cell dynamics, mainly CD4+ regulatory T (Treg) cells, using bioinformatics, flow cytometry, and the influence of gut microbiota through antibiotic treatment and specific bacterial reintroduction.Results: Treatment with hUCMSCs-Exo@Ex-4 significantly improved key DN markers, including blood glucose and proteinuria, alleviating kidney damage. A notable decrease in natural Treg cell infiltration in DN was observed, while Ex-4-loaded exosomes promoted CD4+ Treg cell induction. The therapeutic benefits of hUCMSCs-Exo@Ex-4 were diminished upon CD4+ Treg cell depletion, underscoring their role in this context. Notably, CD4+ Treg cell induction correlated with the presence of Prevotella species, and disruption of gut microbiota adversely affected these cells and the therapeutic efficacy of the treatment. However, the reintroduction of Prevotella strains counteracted these adverse effects.Discussion: This study elucidates a novel therapeutic mechanism of Ex-4-loaded hUCMSCs exosomes in DN, highlighting the induction of CD4+ Treg cells mediated by specific gut microbiota components. These findings underscore the potential of leveraging gut microbiota and immune cell interplay in developing effective DN treatments.
研究领域:
糖尿病
·
肾病学
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干细胞治疗
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免疫学
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微生物组研究
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DOI
PubMed
高影响因子
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