Frontiers in Immunology最新文献

{"title":"HDAC inhibitor MS275 reprograms metabolism to induce differentiation and suppress proliferation in hepatocellular carcinoma.","authors":"Jingjie Li, Cheng Hu, Yuyu Ye, Song Wei, Wenbo Zhu, Jiankai Liang, Jing Cai, Yuan Lin, Liang Peng, Guangmei Yan, Ying Liu","doi":"10.3389/fimmu.2025.1623211","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1623211","url":null,"abstract":"<p><strong>Background: </strong>Histone deacetylase (HDAC) inhibitors have shown therapeutic promise in various cancers, including hepatocellular carcinoma (HCC), due to their ability to regulate cell proliferation, differentiation, and apoptosis. However, their role in metabolic reprogramming and differentiation therapy in HCC remains underexplored.</p><p><strong>Methods: </strong>This study investigated the effects of the HDAC inhibitor MS275 on HCC cells <i>in vitro</i> and <i>in vivo</i>. Cell viability, differentiation marker expression, cell cycle distribution, metabolic activity, and reactive oxygen species (ROS) production were evaluated using CCK-8 assays, qRT-PCR, flow cytometry, Seahorse metabolic analysis, and western blotting. A xenograft mouse model was used to validate <i>in vivo</i> efficacy.</p><p><strong>Results: </strong>MS275 significantly suppressed HCC cell proliferation by inducing G0/G1 phase arrest without triggering apoptosis. MS275 also upregulated hepatocyte-specific markers (GLUL, HNF1A, HNF3A), indicating that it promoted differentiation. Mechanistically, MS275 reprogrammed cellular metabolism by enhancing oxidative phosphorylation and reducing glycolysis, accompanied by increased expression of the metabolic enzyme PKM1. This metabolic shift led to elevated ROS production, which was essential for MS275-induced differentiation. Knockdown of PKM1 abolished both the differentiation and anti-proliferative effects. <i>In vivo</i>, MS275 significantly reduced tumor growth and promoted differentiation without systemic toxicity.</p><p><strong>Conclusion: </strong>MS275 suppresses HCC cell proliferation and induces hepatocyte-like differentiation through PKM1-mediated metabolic reprogramming and ROS signaling. These findings support the potential of MS275 as a differentiation-based therapeutic strategy for HCC.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1623211"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunogenetic investigation of WAS patients revealing impaired IL-6/STAT3 signaling in T cells.","authors":"Firas Bouzakoura, Najla Mekki, Monia Ben Khaled, Ines Maaloul, Aicha Ben Taieb, Amal Zammeli, Meriem Ben-Ali, Mariem Tira, Ansem Ben-Hammadi, Thouraya Kamoun, Monia Ouederni, Mohamed-Ridha Barbouche, Imen Ben-Mustapha","doi":"10.3389/fimmu.2025.1602942","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1602942","url":null,"abstract":"<p><p>Wiskott-Aldrich syndrome (WAS) is an inborn error of immunity caused by loss-of-function mutations in the <i>WAS</i> gene, which encodes WASp, a key regulator of cytoskeletal remodeling. In addition to microthrombocytopenia, affected individuals often present with recurrent infections, eczema, eosinophilia and elevated IgE levels, suggesting a potential pathophysiological overlap with STAT3 hyper-IgE syndrome (HIES). Given these shared features, we investigated the immunogenetic characteristics of three WAS patients and explored the IL-6/STAT3 pathway as a potential underlying mechanism. Flow cytometry revealed absent WASp expression in P1 and P3, while P2 showed reduced level. Genetic analysis identified three hemizygous mutations: A56V substitution within the WH1 domain in P1, and two splice site mutations, c.360 + 1G>T and c.734 + 1G>C, in P2 and P3, respectively. Interestingly, all WAS patients showed impaired STAT3 phosphorylation in T cells following IL-6 stimulation and SOCS3 induction was markedly decreased. These results further suggest a potential link between WASp and STAT3. Considering the interaction of WASp with DOCK8-WIP in lymphocytes and the critical role of DOCK8 in regulating STAT3 phosphorylation following IL-6 stimulation, we analyzed DOCK8 expression in lymphoblastoid cell lines. We demonstrated normal DOCK8 levels suggesting that STAT3 signaling defect is due to the absence of WASp rather than DOCK8 loss. Our results demonstrate the impairment of T cell IL-6/STAT3 pathway in WAS patients which could underlie, in part, the overlapping phenotype with HIES patients.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1602942"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neoadjuvant chemoimmunotherapy for esophageal squamous cell carcinoma with non-regional cervical lymph node metastasis: a retrospective pilot study.","authors":"Chufeng Zeng, Guozhen Yang, Lingyu Tan, Kun Li, Wenyu Zhai, Xin Zhang, Longgao Liu, Weihua Wu, Xiaodong Su, Jianhua Fu, Xu Zhang, Wei Wei Liu","doi":"10.3389/fimmu.2025.1611108","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1611108","url":null,"abstract":"<p><strong>Background: </strong>Esophageal squamous cell carcinoma (ESCC) with non-regional cervical lymph node metastasis (CLNM) poses significant therapeutic challenges due to lack of consensus in guidelines and poor outcomes associated with conventional treatment modalities. Recent studies have demonstrated promising efficacy of combined immunotherapy, chemotherapy, and surgery in ESCC; however, the role of this multimodal approach in managing non-regional CLNM-historically considered inoperable-remains unclear.</p><p><strong>Methods: </strong>This retrospective cohort study included 15 patients with thoracic ESCC and non-regional CLNM who underwent neoadjuvant chemoimmunotherapy (nCIT), followed by McKeown esophagectomy with three-field lymphadenectomy between 2020 and 2024. CLNM was confirmed via ultrasound-guided biopsy. Data on pathological response, safety, and survival outcomes were collected and analyzed. Survival analysis was performed using the Kaplan-Meier method.</p><p><strong>Results: </strong>A pathological complete response (pCR) in CLNM was achieved in 93.3% of patients, while the Total pCR (ypT0N0M0) rate (clearance of both primary tumor and metastatic lymph node) was 33.3%. At a median follow-up of 18.0 months, the 1-year disease-free survival (DFS) rate was 91.7%. One patient died during the follow-up period. Postoperative complications occurred in 73.3% of patients, predominantly respiratory events such as atelectasis and pneumonia; only one patient experienced a grade 4 event. Treatment-related adverse events (TRAEs) were mild, with no grade ≥3 TRAEs observed; anemia was the most common TRAEs, occurring in 46.7% of patients.</p><p><strong>Conclusion: </strong>nCIT induces a high cervical nodal response in ESCC with non-regional CLNM and may redefine surgical eligibility for patients with non-regional metastases. The observed 1-year DFS of 91.7% is promising, though long-term outcomes require further validation through prospective studies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1611108"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding mechanistic relationships between IgG titers and Fc effector functions: a computational framework to assess polyfunctionality.","authors":"Suzanne K Shoffner-Beck, Robert M Theisen, Kade E Wong, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayaphan, Stephen Kent, Amy W Chung, Kelly B Arnold","doi":"10.3389/fimmu.2025.1578500","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1578500","url":null,"abstract":"<p><strong>Introduction: </strong>Recent vaccine and infectious disease studies have highlighted the importance of antibodies that activate cellular Fc functions, including antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC), which are mediated by different Fc gamma Receptors (FcγRs). Activation of these functions requires complex overlapping interactions between IgG antibodies, FcγRs, and antigens that can be challenging to deconvolve experimentally.</p><p><strong>Methods: </strong>Here we created an ordinary differential equation model that simultaneously predicted FcγRIIIa immune complexes upstream of ADCC and FcγRIIa immune complexes upstream of ADCP as a function of antigen, IgG, and FcγR concentration and binding properties. We then used the model to dissect mechanisms driving immune complex formation.</p><p><strong>Results: </strong>Model results suggested that the maximum formation of immune complexes would not occur at highest total IgG titers. Instead, higher IgG titers have the potential to decrease FcγRIIIa (ADCC) and/or FcγRIIa (ADCP) immune complexes, due to competition between antibody subclasses for antigen and FcγR binding. We used the model to simulate vaccine boosts of IgG1 or IgG3 in 105 participants from an HIV vaccine trial, and found that boosting IgG1 and IgG3 in combination was not predicted to result in significant changes in either FcγRIIIa (ADCC) or FcγRIIa (ADCP) immune complexes. Surprisingly, simulated boosting of IgG3 alone had the potential to significantly decrease ADCP (p<0.00001), though it would increase ADCC responses. We also illustrated how the model could be used to assess how variability in viral load, FcγR expression, FcγR polymorphisms, and IgG titers across different tissue compartments can lead to differences in FcγRIIIa and FcγRIIa complexes.</p><p><strong>Discussion: </strong>Altogether, these results illustrate how a computational framework provides new quantitative insights into activation of Fc effector functions that could be used to guide future rational design of therapeutic and prophylactic interventions.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1578500"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A taste of one's own medicine: <i>Bacillus velezensis</i> isolated from adult housefly intestines demonstrates effective fly control.","authors":"Ying Li, Shumin Wang, Dawei Yao, Kexin Zhang, Yansong Yin, Xinxin Kong, Jinxiao Li, Lingxia Zeng, Ruiling Zhang, Zhong Zhang","doi":"10.3389/fimmu.2025.1575292","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1575292","url":null,"abstract":"<p><strong>Introduction: </strong><i>Bacillus</i> spp. are widely used as biological agents for managing diseases in crops, livestock, poultry, and aquatic animals. <i>Bacillus velezensis</i>, a novel species within the <i>Bacillus</i> genus, is extensively used in the biological control of animal and plant diseases. However, the association between <i>B. velezensis</i> and insect hosts remains a complex and poorly understood process.</p><p><strong>Methods: </strong>In this study, we utilized a housefly larvae model to investigate the relationship between <i>B. velezensis</i> and houseflies by examining the changes in intestinal microbiota, transcriptomics, and humoral immunity following symbiotic <i>B. velezensis</i> treatment.</p><p><strong>Results: </strong>The results revealed striking dynamic changes in the bacterial community composition of larvae in the treatment group at the genus level. Notably, <i>Providencia</i> and <i>Morganella</i> content increased, while <i>Enterobacter</i> content decreased, leading to inhibited larval growth. Moreover, the bacterial association with the larva significantly impacted the larval transcriptome, modulating the expression of genes involved in various biological pathways, including host growth and development, macronutrient metabolism, and energy production, which are essential for insect development and survival. Oral feeding of <i>B. velezensis</i> also caused significant morphological changes in the larval gut, resulting in notable larval mortality, cell degeneration, shrinkage, and the formation of various vacuoles. Additionally, we observed a significant decrease in immune response in housefly larvae, with a reduction in phenoloxidase activity and melanization ability in treated larvae compared to controls.</p><p><strong>Discussion: </strong>Therefore, <i>B. velezensis</i> can damage the vital functions of housefly larvae and may be utilized as a microecological regulator for the green prevention and control of housefly populations.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1575292"},"PeriodicalIF":5.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report: A rare case of complex Behçet's disease complicated with acute tubular necrosis and IgA nephropathy, coexists with myelodysplastic syndrome, trisomy 8 and intestinal involvement.","authors":"Peipei Zhang, Wen Zhang, Hong Xia, Zhenliang Fan, Junfen Fan, Hongzhen Ma, Chunli Zhang, Shuyan Liu","doi":"10.3389/fimmu.2025.1618495","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1618495","url":null,"abstract":"<p><p>Behçet's disease (BD) is a rare systemic disease in which small-vessel vasculitis impacts multiple bodily organs. It is typically marked by recurrent oral and genital ulcers, uveitis, and cutaneous lesions. However, peripheral vessels, cardiovascular structures, central nervous system, gastrointestinal tract, joints, lungs, or kidneys may be affected as well. Renal involvement, although uncommon, may manifest as proteinuria, hematuria, and varying degrees of renal insufficiency. Herein, we describe a 35-year-old man with longstanding BD, myelodysplastic syndrome (MDS), and trisomy 8. He presented with cutaneous erythema and gastrointestinal bleeding (requiring colonic resection), later developing acute renal failure. Features of both acute tubular necrosis (ATN) and IgA nephropathy appeared on subsequent biopsy. Following continuous renal replacement therapy and intravenous methylprednisolone treatment, there was gradual recovery of renal function. This scenario represents a rare and severe multisystem presentation of BD with complex comorbidities, attributing the observed kidney injury to combined insults as above. Given the persistent and multifaceted nature of BD, early recognition and targeted management of renal complications are essential to preserve functional capacity and improve patient outcomes.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1618495"},"PeriodicalIF":5.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Bone marrow aging and its impact on immunosenescence in neurological diseases.","authors":"Junchi He, William G Kerr, Xingzhi Guo, Dan Xu","doi":"10.3389/fimmu.2025.1697136","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1697136","url":null,"abstract":"","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1697136"},"PeriodicalIF":5.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nerves, nodes, and neoplasia.","authors":"Minjun Wang, Censhan Ran, Quan Liu","doi":"10.3389/fimmu.2025.1674174","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1674174","url":null,"abstract":"<p><p>Tumor immune evasion and incomplete responses to immunotherapy are some of the most significant obstacles in current cancer treatment. Since tumor-draining LNs (tdLNs) are cradles for anti-tumor immunity, and tumor-specific memory cells in tdLNs are the bona fide responders to immune-checkpoint blockade, tdLNs are increasingly valued in oncoimmunology research and cancer treatments. Recent progress has revealed that lymph nodes (LNs) are innervated and regulated by sensory and sympathetic nerve fibers. Because tumor cells, nerves, and immune cells coexist inside tdLNs-sites where anti-tumor immunity is initiated and compromised-it is critical to investigate whether tumor-neuro-immune crosstalk also occurs in these nodes. Although direct evidence in tdLNs is lacking, we synthesize emerging evidence supporting this possibility. We argue that validating this hypothesis will be essential for elucidating immune evasion mechanisms and advancing surgical and immunological strategies against tumors. In this review, we first introduce LN anatomy, highlighting its innervation by sensory and sympathetic fibers. We then examine the neural regulation of immune activities, especially those within LNs and those associated with a tumor context. We further discuss the multifaceted roles of tdLNs in tumor immunology, including orchestration of anti-tumor immunity and local immunosuppression, pre-metastatic LN remodeling, and induction of systemic tumor-specific immune tolerance. Furthermore, we look into tumor-neural interactions from two angles: tumor-induced nerve growth and activation, and neural regulation of tumor progression. Finally, we propose potential tumor-neuro-immune interactions in tdLNs, discuss current perspectives on LN handling in cancer therapy, and discuss clinical implications of the progress summarized in this review.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1674174"},"PeriodicalIF":5.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytotoxic CD4⁺ T-follicular cells may mediate killing against lymphoma cells.","authors":"Yin Xiao, Sigrun S Haeusl, Gaurav Jethva, Johannes Weber, Andreas Rosenwald, Friederike Berberich-Siebelt","doi":"10.3389/fimmu.2025.1657046","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1657046","url":null,"abstract":"<p><p>Recently, we have identified CD4⁺PD-1⁺CXCR5⁺ T-follicular helper (T_FH) cells with a distinct cytotoxic phenotype and named them \"killer T_FH (T_F <b>_K</b> )\" cells. In this study, we aim to elucidate their presence and functional relevance in two different lymphoma subtypes, follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Flow cytometric analysis of tonsillar versus FL-cell suspensions revealed a heightened number of GZMK⁺NKG7/TIA-1⁺ T_F <b>_K</b> cells in the latter, accompanied by a significant increase in T-regulatory and T-follicular regulatory (T_FR) cells. In contrast, DLBCL exhibited a decrease in T_FH and T_FR cell numbers, while concurrently demonstrating heightened frequencies of GZMK⁺TIA-1⁺ and especially GZMB⁺TIA-1⁺ T_F <b>_K</b> cells within the T_FH population. Analysis of single-cell RNA sequencing data confirmed an origin-specific phenotype of T_F <b>_K</b> cells. Immunofluorescence staining of biopsy specimens detected CD4⁺BCL-6⁺TIA-1⁺ T_F <b>_K</b> cells within follicles and germinal centers (GC) in reactive lymph nodes and within their atypical counterparts in malignant lymph nodes. Their propensity to migrate into atypical GCs was more pronounced in higher grade FLs. Furthermore, the release of cytotoxic cargo by degranulation could be induced by stimulation of CD4⁺ cells in cultures of FL and DLBCL suspensions. In line, the direct cytotoxic capacity of T_F <b>_K</b> cells against lymphoma cells was demonstrated by killing assays with isolated cells, underscoring their potential as a prospective therapeutic target in lymphoma control.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1657046"},"PeriodicalIF":5.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial transcriptomics reveals distinct role of monocytes/macrophages with high <i>FCGR3A</i> expression in kidney transplant rejections.","authors":"Yan Chen Wongworawat, Chirag Nepal, Mark Duhon, Wanqiu Chen, Minh-Tri Nguyen, Adam Godzik, Xinru Qiu, Wei Vivian Li, Gary Yu, Rafael Villicana, Craig Zuppan, Michael De Vera, Michael T Eadon, Mark Haas, Charles Wang","doi":"10.3389/fimmu.2025.1654741","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1654741","url":null,"abstract":"<p><strong>Introduction: </strong>Kidney transplant rejections are classified as active antibody mediated rejection (AMR) and cell mediated rejection (TCMR), with AMR primarily driven by antibodies produced by B cells, whereas TCMR is mediated by T lymphocytes that orchestrate cellular immune responses against the graft. Emerging evidence highlights the essential roles of innate immune cells in rejections, especially monocytes/macrophages and natural killer (NK) cells. However, the roles of specific innate immune cell subpopulations in kidney allograft rejection remain incompletely understood.</p><p><strong>Methods: </strong>We performed the spatial transcriptomics using the formalin-fixed paraffin-embedded (FFPE) core needle biopsies from human kidney allografts.</p><p><strong>Results: </strong>We demonstrated that non-rejection, AMR, acute TCMR and chronic active AMR have distinct transcriptomic features. Subclusters of monocytes/macrophages with high <i>Fc gamma receptor IIIA</i> (<i>FCGR3A</i>) expression were identified in C4d-positive active AMR and acute TCMR, and the spatial distribution of these cells corresponded to the characteristic histopathological features. Key markers related to monocyte/macrophage activation and innate alloantigen recognition were upregulated, along with metabolic pathways associated with trained immunity in AMR and TCMR.</p><p><strong>Discussion: </strong>Taking together, these findings revealed that intragraft monocytes/macrophages with high <i>FCGR3A</i> expression play a critical role in kidney transplant rejections.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1654741"},"PeriodicalIF":5.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145199158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}