Journal of immunology最新文献_第6页

HDAC6/Trim21 aggravates macrophage inflammatory response and titanium-induced osteolysis via GSDMD signaling pathway. HDAC6/Trim21通过GSDMD信号通路加重巨噬细胞炎症反应和钛诱导的骨溶解。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-01 DOI: 10.1093/jimmun/vkaf112

Junxi Chen, Taihe Liu, Jiankai Luo, Zhipeng Chen, Yifan Yu, Haopeng Sun, Muyun Tan, Yujun Sun, Shixun Li, Changchuan Li, Yue Ding

{"title":"HDAC6/Trim21 aggravates macrophage inflammatory response and titanium-induced osteolysis via GSDMD signaling pathway.","authors":"Junxi Chen, Taihe Liu, Jiankai Luo, Zhipeng Chen, Yifan Yu, Haopeng Sun, Muyun Tan, Yujun Sun, Shixun Li, Changchuan Li, Yue Ding","doi":"10.1093/jimmun/vkaf112","DOIUrl":"10.1093/jimmun/vkaf112","url":null,"abstract":"Total joint arthroplasty is the optimal method for end-stage osteoarticular diseases, but aseptic loosening reduces long-term success. Our prior research demonstrated that wear particles released from loosened prostheses activate macrophages to secrete proinflammatory cytokines, thereby promoting osteoclast formation and osteolysis. Gasdermin D (GSDMD), a key regulator of pyroptosis, is a core step in the production of inflammatory factors after stimulation of macrophage pattern recognition receptors together with downstream inflammatory pathways, and histone deacetylase 6 (HDAC6)/tripartite motif-containing protein 21 (Trim21) is important in regulating activation. Yet, the specific mechanism of HDAC6/Trim21/GSDMD in wear particle-induced aseptic loosening (AL) requires further illustration. Our study will clarify the mechanism by demonstrating how HDAC6/Trim21 regulates GSDMD-associated signaling pathways in vivo and in vitro. Sterile titanium particles (TiPs) of 1.2 to 10.0 μm were co-incubated with RAW264.7 macrophages. HDAC6 selective inhibitor tubastatin A, HDAC6 overexpressing lentivirus, and Trim21 small interfering RNA were utilized to explore activation of proinflammatory pathways and polarization of macrophages was related. The mouse cranial osteolysis model was constructed to demonstrate HDAC6 regulating TiP-induced osteolysis. Macrophages were stimulated by TiPs to produce interleukin-1β as well as interferon γ, exhibiting M1 polarization. HDAC6 directedly interacted with Trim21, promoting the multiple proinflammatory responses mentioned above via GSDMD, STING pathway, and NLRP3 pathway. In vivo, HDAC6 provoked TiP-induced mice calvaria osteolysis and IL-1β production. HDAC6/Trim21 aggravates macrophage inflammatory response and titanium-induced osteolysis via GSDMD signaling pathway.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2357-2370"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex-dependent influence of LMAN1 on allergen-induced airway hyperresponsiveness. LMAN1对过敏原诱导的气道高反应性的性别依赖性影响。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-01 DOI: 10.1093/jimmun/vkaf126

Lindsay G Swaby, Faith L Sauber, Madelyn H Miller, Mylena C Xavier, Wesley Lim, Peter Daniel Poulson, Xiang Zhu, Bin Zhang, Justine T Tigno-Aranjuez

{"title":"Sex-dependent influence of LMAN1 on allergen-induced airway hyperresponsiveness.","authors":"Lindsay G Swaby, Faith L Sauber, Madelyn H Miller, Mylena C Xavier, Wesley Lim, Peter Daniel Poulson, Xiang Zhu, Bin Zhang, Justine T Tigno-Aranjuez","doi":"10.1093/jimmun/vkaf126","DOIUrl":"10.1093/jimmun/vkaf126","url":null,"abstract":"Allergic asthma is a chronic inflammatory disease of the airways characterized by a type 2-high adaptive immune response towards common aeroantigens such as dust mite, pollen, and animal dander. Despite the advances made toward translation of various biologics into the clinic, the limited efficacy of these therapies in certain populations, combined with the ineligibility of some patients for treatment (clinically or economically), have led to the continued need for the development of more widely effective allergic asthma therapies. Our lab previously identified lectin mannose-binding 1 (LMAN1) as a novel receptor for house dust mite (HDM) and showed that in vitro, LMAN1 downregulated inflammatory NF-κB signaling in DCs in response to HDM. In this follow-up work, we investigated the in vivo relevance of LMAN1 by subjecting LMAN1 knockout (KO) mice and wild type (WT) littermate controls to a model of HDM-induced allergic asthma. Surprisingly, we discovered that loss of LMAN1 led to opposing effects on airway hyperresponsiveness (AHR), which were dependent on the sex of the mice. HDM-treated female LMAN1 KO mice showed increased AHR, while HDM-treated male KO mice showed decreased AHR, compared with their WT counterparts. We further identified the features of HDM-induced asthma which may account for the gender-biased effects of LMAN1 on lung function. This work not only highlights the complexity of the loss of LMAN1 in vivo but also suggests that such sex-dependent responses should be taken into consideration when pursuing LMAN1 as a therapeutic target for treatment of allergic asthma.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2397-2407"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12353830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of statins on IL-10 signaling and production by chronic lymphocytic leukemia cells. 他汀类药物对慢性淋巴细胞白血病细胞IL-10信号传导和产生的影响。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-01 DOI: 10.1093/jimmun/vkaf103

Guizhi Wang, Tina YuXuan Luo, Yonghong Shi, Aditya Surya, Haggag S Zein, Gregory D Fairn, David E Spaner

{"title":"Effect of statins on IL-10 signaling and production by chronic lymphocytic leukemia cells.","authors":"Guizhi Wang, Tina YuXuan Luo, Yonghong Shi, Aditya Surya, Haggag S Zein, Gregory D Fairn, David E Spaner","doi":"10.1093/jimmun/vkaf103","DOIUrl":"10.1093/jimmun/vkaf103","url":null,"abstract":"The cytokine-signaling inhibitor ruxolitinib causes disease flares of chronic lymphocytic leukemia (CLL). This tumor-promoting activity correlates with its ability to inhibit interleukin (IL)-10 production by CLL B cells that have been activated with IL-2 and the Toll-like receptor 7 (TLR7) agonist resiquimod (called 2S cells) in vitro. In TLR-activated normal human B cells, IL-10 production is regulated by cholesterol biosynthesis and can be inhibited by statins. The goal of this study was to determine if statins affect IL-10 production by 2S cells. Lipophilic statins decreased IL-10 production from 2S CLL cells by inhibiting activation of MYC along with secondary signaling events that amplify and maintain IL10 transcription. IL-10 production was restored when the prenylation defect imposed by statins was corrected by adding geranylgeranyl pyrophosphate. CLL cells activated by ruxolitinib in vivo were enriched with genes associated with prenylation inhibition in TLR-activated human B cells in vitro. These findings suggest IL-10 production by 2S-activated CLL cells is regulated by cholesterol biosynthesis in part through geranylgeranyl pyrophosphate production and substrate prenylation. If IL-10 production in the 2S model constitutes a surrogate test for drug responses in vivo, realization of the potential clinical benefits of statins in CLL may require coadministration of other agents.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2453-2463"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Borrelia burgdorferi c-di-AMP is a key extracellular pathogen-associated molecular pattern to elicit type I interferon responses in mammalian hosts. 伯氏疏螺旋体c- 2 - amp是在哺乳动物宿主中引发I型干扰素反应的关键细胞外病原体相关分子模式。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-01 DOI: 10.1093/jimmun/vkaf133

Raj Priya, Meiping Ye, Sajith Raghunanadanan, Qiang Liu, Wei Li, Qigui Yu, Yongliang Lou, Herman O Sintim, X Frank Yang

{"title":"Borrelia burgdorferi c-di-AMP is a key extracellular pathogen-associated molecular pattern to elicit type I interferon responses in mammalian hosts.","authors":"Raj Priya, Meiping Ye, Sajith Raghunanadanan, Qiang Liu, Wei Li, Qigui Yu, Yongliang Lou, Herman O Sintim, X Frank Yang","doi":"10.1093/jimmun/vkaf133","DOIUrl":"10.1093/jimmun/vkaf133","url":null,"abstract":"Borrelia burgdorferi (or Borreliella burgdorferi), the extracellular spirochete responsible for Lyme disease, elicits a type I interferon (IFN-I) response critical for the development of Lyme arthritis. However, the specific pathogen-associated molecular pattern (PAMP) driving this response remains unidentified. Previous studies have reported that B. burgdorferi culture supernatants significantly stimulate macrophage IFN-I responses, but the responsible component was unknown. In this study, we identified cyclic-di-adenosine monophosphate (c-di-AMP) as the critical PAMP for the induction of IFN response. Inactivation of cdaA, which encodes diadenylate cyclase for c-di-AMP synthesis, significantly reduced IFN-β production in murine macrophage cell lines (RAW264.7) and bone marrow-derived macrophages. Conversely, the deletion of dhhP, which encodes c-di-AMP phosphodiesterase, dramatically increased IFN-β production. We further demonstrated that B. burgdorferi releases c-di-AMP, which is the major component in the culture supernatant responsible for stimulating the IFN-I response in macrophages. Furthermore, B. burgdorferi c-di-AMP-induced IFN-I response depends on STING, as inactivation or inhibition of STING signaling markedly reduced IFN-I induction. These findings establish c-di-AMP as a key PAMP of B. burgdorferi that activates host STING signaling to induce IFN-I responses, highlighting its potential as a therapeutic target for Lyme arthritis.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2325-2337"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genomic specificity of anti-mouse TCR mAbs determined by single-cell RNAseq. 单细胞RNAseq测定抗小鼠TCR单抗的基因组特异性。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-01 DOI: 10.1093/jimmun/vkaf094

Ian Magill, Val Piekarsa, Sofia Kossida, Josh Croteau, Amy Lee, Robert Balderas, David Zemmour, Christophe Benoist

{"title":"Genomic specificity of anti-mouse TCR mAbs determined by single-cell RNAseq.","authors":"Ian Magill, Val Piekarsa, Sofia Kossida, Josh Croteau, Amy Lee, Robert Balderas, David Zemmour, Christophe Benoist","doi":"10.1093/jimmun/vkaf094","DOIUrl":"10.1093/jimmun/vkaf094","url":null,"abstract":"T cells play a pivotal role in the immune system, relying on their somatically rearranged T cell receptor (TCR) to recognize peptide-MHC complexes. A comprehensive and extensively used set of monoclonal antibodies (mAbs) against TCR variable regions was generated in the previous century. The separate identification of mAb-specific TCR-V proteins and TRV genes has resulted in multiple nomenclatures, making their relationships unclear. To formally re-establish this link and determine patterns of reactivity within TRV subfamilies, we sorted T cells from C57BL/6 mice positive for any one of a panel of 22 anti-V mAbs and determined their TRV genes by single-cell TCRseq. RNAseq data revealed consistently higher expression of repeated elements from the ERV1-family LTR RLTR6Mm (mapping to Gm20400) in cells utilizing TRBV segments encoded within a 66 kb genomic region between TRBV23 and TRBV30. Our findings provide a comprehensive resource for anti-mouse TCR mAb specificity and insight into V-gene usage biases and T cell function.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2202-2210"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mallard ILF2 negatively regulates type I IFN production through autophagy-lysosome-dependent degradation of IRF7. 野鸭ILF2通过自噬-溶酶体依赖的IRF7降解负向调节I型IFN的产生。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-01 DOI: 10.1093/jimmun/vkaf118

An Ning Pang, Shan Nan Chen, Bin Tian, Lan Hao Liu, Shan Zhang, Jing Wei Song, Pin Nie

{"title":"Mallard ILF2 negatively regulates type I IFN production through autophagy-lysosome-dependent degradation of IRF7.","authors":"An Ning Pang, Shan Nan Chen, Bin Tian, Lan Hao Liu, Shan Zhang, Jing Wei Song, Pin Nie","doi":"10.1093/jimmun/vkaf118","DOIUrl":"10.1093/jimmun/vkaf118","url":null,"abstract":"Interleukin enhancer-binding factor 2 (ILF2) has been reported to act as either a positive or negative regulator of viral infection by directly affecting viral RNA replication. In this study, mallard ILF2 was found to impair type I IFN production, thereby facilitating the replication of duck Tembusu virus (DTMUV). The overexpression of ILF2 in duck embryo fibroblast (DEF) cells resulted in suppression of polyI: C- and DTMUV-induced production of three type I interferons (IFNs), IFN-α, IFN-β, IFN-κ-like, whereas the knockdown of ILF2 expression in DEF cells enhanced type I IFN production and inhibited DTMUV infection. It is also found that the zinc finger-related domain (DZF) of ILF2 interacts with the IRF association domain (IAD) of IRF7, and ILF2 may cause autophagic degradation of IRF7 at the protein level. Furthermore, ILF2 was found to interact also with Beclin1, and Beclin1 is necessary for ILF2-induced IRF7 degradation as ILF2-induced IRF7 degradation was significantly restored after knockdown of Beclin1. These results provide obvious evidence that ILF2 recruits Beclin1 to degrade IRF7, resulting in the suppression of type I IFN production in DEF cells.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2371-2384"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

LAG3-MHCII interaction induces a tight cell-cell interface at the immunological synapse. LAG3-MHCII相互作用在免疫突触诱导紧密的细胞-细胞界面。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-01 DOI: 10.1093/jimmun/vkaf120

Zibin Wang, Ting Zhou, Hanbing Wang, He Li, Wene Zhao, Feng Wang, Yan Li, Wen Liu, Jia Wei, Xianchi Dong

{"title":"LAG3-MHCII interaction induces a tight cell-cell interface at the immunological synapse.","authors":"Zibin Wang, Ting Zhou, Hanbing Wang, He Li, Wene Zhao, Feng Wang, Yan Li, Wen Liu, Jia Wei, Xianchi Dong","doi":"10.1093/jimmun/vkaf120","DOIUrl":"10.1093/jimmun/vkaf120","url":null,"abstract":"Lymphocyte activation gene 3 (LAG3), an immune checkpoint, inhibits T cell function by binding to major histocompatibility complex class II (MHCII). Although LAG3 holds significant therapeutic potential for cancer immunotherapy, the molecular mechanisms underlying LAG3-mediated immunosuppression remain poorly characterized. Here, using a reconstituted cell conjugation assay, we demonstrate that LAG3 binds directly to MHCII in a T cell receptor signaling-independent manner. Beyond its role in modulating intercellular adhesion, the LAG3-MHCII interaction remodels the architecture of the immunological synapse (IS). Correlative light and electron microscopy reveals that the LAG3-MHCII interaction creates a remarkably tight cell-cell interface at the IS, which selectively excludes CD4, large receptor-ligand complexes, and whole IgG of LAG3 antibodies. Conversely, the Fab fragment of LAG3 antibodies can penetrate this tight interface, block LAG3-MHCII binding, and enhance T cell responses. In addition, the LAG3-MHCII interaction directly facilitates MHCII trogocytosis. These findings demonstrate that the LAG3-MHCII interaction establishes a selective physical barrier at the IS, providing novel mechanistic insights into LAG3-mediated immunosuppression and suggesting feasible strategies for the development of more effective immunotherapeutic drugs.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2256-2269"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

G9a controls plasma cell differentiation through FOXO1 and ETS1 binding site regulatory networks. G9a通过FOXO1和ETS1结合位点调控网络控制浆细胞分化。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-01 DOI: 10.1093/jimmun/vkaf127

Lou-Ella M M George-Alexander, Roshni Roy, Anna K Kania, Sakeenah L Hicks, Mansi Gupta, Christopher D Scharer, Jeremy M Boss

{"title":"G9a controls plasma cell differentiation through FOXO1 and ETS1 binding site regulatory networks.","authors":"Lou-Ella M M George-Alexander, Roshni Roy, Anna K Kania, Sakeenah L Hicks, Mansi Gupta, Christopher D Scharer, Jeremy M Boss","doi":"10.1093/jimmun/vkaf127","DOIUrl":"10.1093/jimmun/vkaf127","url":null,"abstract":"B cell differentiation is tightly regulated through coordinated changes in metabolism, division, expression of transcription factors, and epigenetic programming mediated by histone modifying enzymes. Here, we examined the role of an epigenetic writer, the histone H3K9 mono and dimethyltransferase G9a, in B cell development and plasma cell (PC) formation in vivo. Utilizing a B cell specific G9afl/flCd19Cre/+ conditional mouse model we found a significant decrease of marginal zone B cells in G9a knockout (KO) mice. When challenged with a T cell-independent antigen LPS, these mice displayed increased frequencies of activated B cells and plasma cells. Compared to control mice, G9a KO activated B cells divided fewer times before expressing the plasma cell marker CD138. RNA-seq and ATAC-seq revealed dysregulation of genes involved in regulating proliferation and PC function. Integrated bioinformatics analyses identified potential transcription factor targets of G9a as FOXO1, ETS1, and ELF1 as their putative target genes were dysregulated, thereby providing a potential mechanism for how these pathways are controlled. Importantly G9a deficiency was associated with genes that were both up and down modulated, highlighting distinct regulatory modes of action. Together, these data show that G9a is critical to the fate and restricts specific aspects of plasma cell formation, providing a unique set of target genes that could be manipulated in therapies aimed at controlling B cell and PC function or formation.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2408-2424"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PGI2 signaling metabolically reprograms CD4 Th2 cells and represses allergic airway inflammation. PGI2信号代谢重编程CD4 Th2细胞和抑制过敏性气道炎症。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-01 DOI: 10.1093/jimmun/vkaf130

Weisong Zhou, Jian Zhang, Nowrin U Chowdhury, Allison E Norlander, Shinji Toki, Masako Abney, Mark Rusznak, Katherine N Gibson-Corley, Daniel P Cook, Dawn C Newcomb, Ray Stokes Peebles

{"title":"PGI2 signaling metabolically reprograms CD4 Th2 cells and represses allergic airway inflammation.","authors":"Weisong Zhou, Jian Zhang, Nowrin U Chowdhury, Allison E Norlander, Shinji Toki, Masako Abney, Mark Rusznak, Katherine N Gibson-Corley, Daniel P Cook, Dawn C Newcomb, Ray Stokes Peebles","doi":"10.1093/jimmun/vkaf130","DOIUrl":"10.1093/jimmun/vkaf130","url":null,"abstract":"Prostaglandin I2 (PGI2) is a lipid mediator known to inhibit T helper 2 (Th2) immune responses and allergic inflammation, but its role in regulating Th2 cell metabolism remains underexplored. Using the Seahorse assay, we evaluated the effects of PGI2 signaling on Th2 cell glycolysis and mitochondrial respiration. Our results show that cicaprost, a stable PGI2 analog, significantly reduced basal, maximal, and spare glycolytic capacities in wild-type Th2 cells, while these effects are absent in Th2 cells lacking the PGI2 IP receptor (IP knockout [KO]). Cicaprost also impaired mitochondrial respiration and adenosine triphosphate production in wild-type Th2 cells, but not in IP KO cells, indicating that PGI2 signaling is essential for these metabolic changes. Further analysis revealed that cicaprost decreased glucose transporter 1 expression and glucose uptake and inhibited mitochondrial mass and membrane potential, suggesting that PGI2 signaling inhibits Th2 cell metabolism by reducing glucose availability and mitochondrial respiratory functions. Metabolomic profiling of cicaprost-treated Th2 cells showed dose-dependent changes, with 126 downregulated and 233 upregulated metabolites showing over 2-fold significant changes compared with vehicle-treated cells. Pathway analysis of these altered metabolites suggests a shift from catabolism to anabolism in cicaprost-treated Th2 cells. In vivo, CD4-specific conditional IP KO mice (CD4Cre+IPflox) exhibited exacerbated lung inflammation following exposure to Alternaria alternata extract, marked by increased IL-5 and IL-13 production, enhanced eosinophilia, and elevated mucus production. These findings establish a mechanistic link between PGI2-mediated immunoregulation and metabolic reprogramming, reinforcing its role as a key modulator of allergic inflammation.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2270-2280"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cytokine and metabolite networks shape T cell residency and functionality at the term human maternal-fetal interface. 细胞因子和代谢物网络塑造了T细胞在母体-胎儿界面的驻留和功能。

IF 3.4 3区医学

Journal of immunology Pub Date : 2025-09-01 DOI: 10.1093/jimmun/vkaf093

Nicholas J Maurice, Jami R Erickson, Caitlin S DeJong, Florian Mair, Alexis K Taber, Marie Frutoso, Laura V Islas, Anna Lena B G Vigil, Richard L Lawler, Juliana McElrath, Evan Newell, Lucas B Sullivan, Raj Shree, Stephen A McCartney

{"title":"Cytokine and metabolite networks shape T cell residency and functionality at the term human maternal-fetal interface.","authors":"Nicholas J Maurice, Jami R Erickson, Caitlin S DeJong, Florian Mair, Alexis K Taber, Marie Frutoso, Laura V Islas, Anna Lena B G Vigil, Richard L Lawler, Juliana McElrath, Evan Newell, Lucas B Sullivan, Raj Shree, Stephen A McCartney","doi":"10.1093/jimmun/vkaf093","DOIUrl":"10.1093/jimmun/vkaf093","url":null,"abstract":"Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI), which affect T cell programming, but the identities (i.e. memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as proinflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of costimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although proinflammatory molecules elicit T cell effector functions, we show that additional cytokine (transforming growth factor β1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, these data demonstrate that T cells at the MFI are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments in which they are enriched.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":"2221-2237"},"PeriodicalIF":3.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0