Journal of immunology最新文献

Butyrate receptor HCAR2/GPR109A controls imiquimod-induced psoriasis-like skin inflammation. 丁酸盐受体HCAR2/GPR109A控制吡喹莫德诱导的牛皮癣样皮肤炎症。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-05-28 DOI: 10.1093/jimmun/vkaf069

Lucija Leko, Darija Šimić, Timna Valera Martins, Gabriel Victor Lucena da Silva, Isabelle Maillet, Florence Savigny, Lara Vuksan, Dorian de Moura Rodrigues, Marc Le Bert, Stefan Offermanns, Nicolas Riteau, Dieudonnée Togbe, Valerie F Quesniaux, Remo Castro Russo, José Carlos Alves-Filho, Bernhard Ryffel

{"title":"Butyrate receptor HCAR2/GPR109A controls imiquimod-induced psoriasis-like skin inflammation.","authors":"Lucija Leko, Darija Šimić, Timna Valera Martins, Gabriel Victor Lucena da Silva, Isabelle Maillet, Florence Savigny, Lara Vuksan, Dorian de Moura Rodrigues, Marc Le Bert, Stefan Offermanns, Nicolas Riteau, Dieudonnée Togbe, Valerie F Quesniaux, Remo Castro Russo, José Carlos Alves-Filho, Bernhard Ryffel","doi":"10.1093/jimmun/vkaf069","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf069","url":null,"abstract":"Psoriasis is a chronic inflammatory skin disorder characterized by aberrant keratinocyte proliferation and immune cell infiltration with upregulation of inflammatory cytokines. Here, we examined the contribution of HCAR2 encoding for the short-chain fatty acid receptor GPR109A. Human and mouse RNA sequencing public datasets reveal elevated HCAR2 gene expression in psoriatic as compared with healthy skin, both in keratinocytes and myeloid cells. Immunostaining and flow cytometry of imiquimod-induced psoriatic-like lesions in Hcar2-mRFP reporter mice showed increased GPR109A expression by keratinocytes and inflammatory cells. GPR109A-deficient mice demonstrated a more severe imiquimod-induced psoriasis-like response than wild-type mice, with exacerbated epidermal hyperplasia, dermal inflammatory cell infiltration, and increased inflammatory mediators myeloperoxidase, CXCL5, LCN2, interleukin (IL)-1β, IL-6, IL-23, and IL-17A. Conversely, topical administration of sodium butyrate reduced imiquimod-induced skin inflammation in wild-type mice, but not in GPR109A-deficient mice. Mechanistically, GPR109A agonist butyrate inhibits histone deacetylase 3, thus inhibiting IL-1β and the inflammatory IL-1β/IL-23/IL-17A axis in imiquimod-induced skin inflammation. Therefore, GPR109A may have a protective role in psoriasis pathogenesis, supporting a potential therapeutic benefit of sodium butyrate administration or other GPR109A agonists for treating psoriasis.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159628","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

Comprehensive analysis of immune checkpoint molecules profiles phenotype and function of exhausted T cells in enzootic bovine leukosis. 牛地方性白血病耗竭T细胞免疫检查点分子、表型和功能的综合分析。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-05-27 DOI: 10.1093/jimmun/vkaf050

Hayato Nakamura, Satoru Konnai, Tomohiro Okagawa, Naoya Maekawa, Wisa Tiyamanee, Mari Ikehata, Koume Matsubara, Kei Watari, Kana Kamitani, Maya Saito, Yukinari Kato, Yasuhiko Suzuki, Shiro Murata, Kazuhiko Ohashi

{"title":"Comprehensive analysis of immune checkpoint molecules profiles phenotype and function of exhausted T cells in enzootic bovine leukosis.","authors":"Hayato Nakamura, Satoru Konnai, Tomohiro Okagawa, Naoya Maekawa, Wisa Tiyamanee, Mari Ikehata, Koume Matsubara, Kei Watari, Kana Kamitani, Maya Saito, Yukinari Kato, Yasuhiko Suzuki, Shiro Murata, Kazuhiko Ohashi","doi":"10.1093/jimmun/vkaf050","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf050","url":null,"abstract":"Bovine leukemia virus (BLV) causes enzootic bovine leukosis (EBL), a B-cell lymphoma in cattle. Previous studies have demonstrated that T cells of BLV-infected cattle show increased expression of immune checkpoint molecules, including programmed death-1 (PD-1), lymphocyte-activation gene-3 (LAG-3), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and T-cell immunoglobulin domain and mucin domain-3 (TIM-3), leading to T-cell exhaustion. However, the key immune checkpoint molecules driving T-cell exhaustion in BLV-induced tumorigenesis remained unclear. In this study, we identified the key immune checkpoint molecules by performing comprehensive flow cytometric analyses of T cells from EBL cattle, and elucidated the phenotype and function of exhausted T cells using a transcriptomic analysis by RNA sequencing and cell culture assays. The comprehensive expression analysis revealed that the proportion of CD4+ and CD8+ T cells co-expressing PD-1 and TIM-3 was significantly increased in the peripheral blood and tumor tissues of EBL cattle compared to healthy cattle. Transcriptomic analysis of PD-1+TIM-3+ T cells revealed the upregulation of genes related to terminal exhaustion and the downregulation of genes related to T-cell differentiation and response in this subset. Additionally, PD-1+TIM-3+ T cells exhibited higher expression of CTLA-4, LAG-3, and Eomes, and lower expression of T-bet, suggesting a terminally exhausted phenotype. Cell culture assays revealed a significant impairment in IFN-γ production in PD-1+TIM-3+ T cells upon stimulation, reflecting severe dysfunction. These findings indicate that PD-1+TIM-3+ T cells play a central role in T-cell exhaustion during BLV-induced tumorigenesis. This study provides valuable insights for future therapeutic strategies against BLV infection.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144150771","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

Myeloid-specific HNRNPA2B1 deficiency disrupts macrophage function and in vivo responses. 骨髓特异性HNRNPA2B1缺乏破坏巨噬细胞功能和体内反应。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-05-25 DOI: 10.1093/jimmun/vkaf073

Mays Mohammed Salih, Chi G Weindel, Eric Malekos, Lisa Sudek, Sol Katzman, Cory J Mabry, Morgan J Chapman, Aja K Coleman, Sikandar Azam, Robert O Watson, Kristin L Patrick, Susan Carpenter

{"title":"Myeloid-specific HNRNPA2B1 deficiency disrupts macrophage function and in vivo responses.","authors":"Mays Mohammed Salih, Chi G Weindel, Eric Malekos, Lisa Sudek, Sol Katzman, Cory J Mabry, Morgan J Chapman, Aja K Coleman, Sikandar Azam, Robert O Watson, Kristin L Patrick, Susan Carpenter","doi":"10.1093/jimmun/vkaf073","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf073","url":null,"abstract":"The mechanisms through which heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) contributes to innate immune gene regulation are poorly understood. To fill this gap, we generated a myeloid lineage-specific HNRNPA2B1-conditional mouse using LysMCre. In an endotoxic shock model, HNRNPA2B1-deficient mice exhibit dampened expression of inflammatory mediators despite increased infiltration of macrophages and neutrophils. Likewise, during infection with the gram-negative bacterial pathogen Salmonella enterica, HNRNPA2B1-deficient mice fail to mount protective inflammatory responses and experience higher bacterial burdens. To better understand the molecular mechanisms driving these phenotypes in vivo, we performed transcriptomics analysis of LPS-treated HNRNPA2B1-deficient macrophages ex vivo. We noted an increase in transcripts encoding nonproductive isoforms of a number of Interferon (IFN)-regulated genes, including the IFNG receptor (IFNGR). Focusing on IFNGR, we confirmed lower surface expression on HNRNPA2B1-deficient macrophages and dampened responsiveness in response to IFNG treatment. In conclusion, our data demonstrates that HNRNPA2B1 is essential for optimal macrophage function, particularly in the context of intracellular bacterial restriction in the case of Salmonella infection. This highlights a previously unappreciated role for RNA-binding proteins in mounting effective immune defenses.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142242","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

The negative impacts of "impact". “冲击”的负面影响。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-05-25 DOI: 10.1093/jimmun/vkaf106

Gail A Bishop

引用次数: 0

CXCL14 is an essential modulator of TLR9 agonist-induced antitumor immune responses. CXCL14是TLR9激动剂诱导的抗肿瘤免疫反应的重要调节剂。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-05-23 DOI: 10.1093/jimmun/vkaf080

Kosuke Tanegashima, Eiji Esashi, Koji Ishida, Ayumi Kotaki, Rina Iwase, Manaka Hasebe, Rena Takahashi, Risa Saito, Yasuhiro Kazuki, Teruhiko Suzuki, Takahiko Hara

{"title":"CXCL14 is an essential modulator of TLR9 agonist-induced antitumor immune responses.","authors":"Kosuke Tanegashima, Eiji Esashi, Koji Ishida, Ayumi Kotaki, Rina Iwase, Manaka Hasebe, Rena Takahashi, Risa Saito, Yasuhiro Kazuki, Teruhiko Suzuki, Takahiko Hara","doi":"10.1093/jimmun/vkaf080","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf080","url":null,"abstract":"Cancer immunotherapeutic CpG oligodeoxynucleotide (ODN) is an agonist for TLR9 and a potent inducer of inflammatory cytokines and type I interferon. Clinical trials of CpG ODNs highlight the urgent need for effective TLR9 agonist CpG ODNs in humans. Here, we developed a highly potent CpG ODN, A602, which induces antitumor immune responses in combination with CXCL14. A602 induced secretion of interferon-α by human peripheral blood mononuclear cells. In mouse macrophages, dendritic cells, and human plasmacytoid dendritic cell lines, CXCL14 enhanced cellular uptake of A602, thereby promoting TLR9-mediated immune responses. Importantly, A602 exhibited strong antitumor activity in syngeneic mouse models of colorectal cancer-derived CT26, B lymphoma-derived A20, and melanoma-derived B16F10 cells. Because the antitumor effect of A602 against B16F10 cells was negated in Cxcl14 knockout mice, endogenously expressed CXCL14 is required for the A602-mediated tumor suppression. Thus, modulation of CXCL14 during the A602-induced immune responses shall unveil an innovative new approach for the antitumor immune therapy.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127848","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

Diagnostic potential of MMP-9, IL-8, and MPO in bronchoalveolar lavage fluid as combined biomarkers for pediatric post-infectious bronchiolitis obliterans. 支气管肺泡灌洗液中MMP-9、IL-8和MPO作为小儿感染后闭塞性细支气管炎联合生物标志物的诊断潜力

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-05-23 DOI: 10.1093/jimmun/vkaf102

Saiping Huang, Guoyuan Wu, Tianfu Xu, Dong Lin, Zhijian Zhan

{"title":"Diagnostic potential of MMP-9, IL-8, and MPO in bronchoalveolar lavage fluid as combined biomarkers for pediatric post-infectious bronchiolitis obliterans.","authors":"Saiping Huang, Guoyuan Wu, Tianfu Xu, Dong Lin, Zhijian Zhan","doi":"10.1093/jimmun/vkaf102","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf102","url":null,"abstract":"This study investigates the diagnostic potential of matrix metalloproteinase-9 (MMP-9), IL-8, and myeloperoxidase (MPO) in bronchoalveolar lavage fluid (BALF) as combined biomarkers for post-infectious bronchiolitis obliterans (PIBO) in children. BALF samples from children with PIBO were analyzed using ELISA to quantify MMP-9, IL-8, and MPO levels. Receiver operating characteristic (ROC) curves were used to assess their diagnostic values, while Pearson correlation analysis examined their associations with lung function and inflammation markers. A PIBO mouse model was established via nebulized nitric acid inhalation, and targeted inhibition of MMP-9, IL-8, and MPO using small interfering RNAs (siRNAs) was performed given via intratracheal administration. The effects on airway inflammation and pathological lung changes were evaluated. Bioinformatics analysis identified upstream microRNAs (miRNAs) regulating MMP-9, IL-8, and MPO, which were validated using dual-luciferase assay and Western blotting. Results revealed significant upregulation of MMP-9, IL-8, and MPO in the BALF of children with PIBO. Combined detection of these biomarkers demonstrated high diagnostic accuracy. MMP-9, IL-8, and MPO levels in BALF were negatively correlated with lung function indicators but positively correlated with inflammatory factors. Targeted inhibition of these molecules reduced airway hyperresponsiveness and inflammation in PIBO mice. miR-766-3p was downregulated in the lung tissues of PIBO mice and in the BALF of affected children, showing a negative correlation with MMP-9, IL-8, and MPO. Functional assays confirmed that miR-766-3p directly targeted MMP-9, IL-8, and MPO. In conclusion, MMP-9, IL-8, and MPO serve as reliable combined biomarkers for PIBO diagnosis and may aid in early clinical identification. miR-766-3p is an upstream miRNA for MMP-9, IL-8, and MPO.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127851","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

Modulatory effects of M3 muscarinic acetylcholine receptor on inflammatory profiles of human memory T helper cells. M3毒蕈碱乙酰胆碱受体对人记忆T辅助细胞炎症谱的调节作用。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-05-22 DOI: 10.1093/jimmun/vkaf086

Fatemeh Gholizadeh, Mehri Hajiaghayi, Jennifer S Choi, Samuel R Little, Niloufar Rahbari, Melika Kargar, Kelly Brotto, Eric Han, Steve C C Shih, Peter J Darlington

{"title":"Modulatory effects of M3 muscarinic acetylcholine receptor on inflammatory profiles of human memory T helper cells.","authors":"Fatemeh Gholizadeh, Mehri Hajiaghayi, Jennifer S Choi, Samuel R Little, Niloufar Rahbari, Melika Kargar, Kelly Brotto, Eric Han, Steve C C Shih, Peter J Darlington","doi":"10.1093/jimmun/vkaf086","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf086","url":null,"abstract":"Memory T helper (Th) cells, generated in response to immunogenic challenges, are crucial in orchestrating adaptive immune responses. Acetylcholine (ACh), a key neurotransmitter of the parasympathetic nervous system, modulates immune function via muscarinic ACh receptors (mAChRs). This study investigates the role of mAChRs, particularly the M3 muscarinic ACh receptor (M3R), in regulating the cytokine and chemokine profile and NF-κB p65 activity in primary human memory Th cells. Memory Th cells were isolated from healthy donors and stimulated with anti-CD3/CD28/CD2 in the presence of oxotremorine-M (M1R-M5R agonist), atropine (M1R-M5R antagonist), or J104129 (M3R-selective antagonist). CHRM1-CHRM5 expression was quantified using RT-qPCR. M3R and phosphorylated NF-κB p65 were analyzed by Western blot. IFN-γ, IL-17A, and IL-4 were assessed by ELISA, while intracellular cytokine and chemokine receptor expression were measured by flow cytometry. CHRM3 knockout was performed using CRISPR-Cas9. Memory Th cells expressed all 5 mAChR subtypes. Oxotremorine-M increased IFN-γ and IL-17A while reducing IL-4 in an atropine-sensitive manner. Blocking or knocking out M3R prevented oxotremorine-M-induced increases in IFN-γ and IL-17A, but the suppression of IL-4 remained unchanged. Stimulation of mAChRs, particularly M3R, enhanced NF-κB p65 activity but did not affect chemokine receptor expression, cell proliferation, viability, or M3R levels. These findings indicate that mAChRs, including M3R, drive a pro-inflammatory memory Th-cell response through NF-κB p65 activation, while IL-4 suppression occurs independently of M3R. Targeting M3R specifically may provide a strategy for modulating adaptive immunity and treating inflammatory diseases.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127855","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

Specific thresholds of circulating antibody titers predict against infection and reduced disease severity in SARS-CoV-2 close contacts. 循环抗体滴度的特定阈值预测SARS-CoV-2密切接触者的感染和疾病严重程度降低。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-05-22 DOI: 10.1093/jimmun/vkaf101

Joanne Byrne, Colette Marie Gaillard, Lili Gu, Alejandro Garcia-Leon, Orlaith Casey, Grace Kenny, Gurvin Saini, Dana Alalwan, Tessa O'Gorman, Siobhan O'Regan, Peter Doran, Eoin R Feeney, Jane A O'Halloran, Mary Horgan, Aoife G Cotter, Eoghan de Barra, Corinna Sadlier, Alan Landay, Virginie Gautier, Patrick W G Mallon

{"title":"Specific thresholds of circulating antibody titers predict against infection and reduced disease severity in SARS-CoV-2 close contacts.","authors":"Joanne Byrne, Colette Marie Gaillard, Lili Gu, Alejandro Garcia-Leon, Orlaith Casey, Grace Kenny, Gurvin Saini, Dana Alalwan, Tessa O'Gorman, Siobhan O'Regan, Peter Doran, Eoin R Feeney, Jane A O'Halloran, Mary Horgan, Aoife G Cotter, Eoghan de Barra, Corinna Sadlier, Alan Landay, Virginie Gautier, Patrick W G Mallon","doi":"10.1093/jimmun/vkaf101","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf101","url":null,"abstract":"Higher circulating SARS-CoV-2 IgG titers correlate with SARS-CoV-2 ex vivo viral neutralization, but how well this translates to clinical protection in the real-world setting is unclear. In a prospective cohort study, we enrolled 44 SARS-CoV-2 negative, confirmed SARS-CoV-2 close contacts. Receptor-binding domain (RBD) and full-spike IgG and SARS-CoV-2 memory B-cell frequencies were measured at exposure, and participants were serially tested for incident infection over 14 days. Those who developed SARS-CoV-2 infection had significantly lower RBD titers, but not memory B-cell frequencies. An RBD IgG titer >6321 BAU/ml was associated with a reduced SARS-CoV-2 acquisition risk (HR 0.32, 95% CI 0.13-0.81), while an RBD IgG titer >456 BAU/ml was associated with a reduced moderate or severe COVID-19 risk (HR 0.15, 95% CI 0.03-0.81), identifying this threshold as a correlate of protection.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127857","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

H3 hemagglutinin proteins optimized for 2018 to 2022 elicit neutralizing antibodies across panels of modern influenza A(H3N2) viruses. 针对2018年至2022年优化的H3血凝素蛋白在现代甲型流感（H3N2）病毒组中引发中和抗体。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-05-21 DOI: 10.1093/jimmun/vkaf092

James D Allen, Jessica M Medina, Matthew H Thomas, Amanda Lynch, Ron Nelson, Julia Aguirre, Ted M Ross

{"title":"H3 hemagglutinin proteins optimized for 2018 to 2022 elicit neutralizing antibodies across panels of modern influenza A(H3N2) viruses.","authors":"James D Allen, Jessica M Medina, Matthew H Thomas, Amanda Lynch, Ron Nelson, Julia Aguirre, Ted M Ross","doi":"10.1093/jimmun/vkaf092","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf092","url":null,"abstract":"Influenza A(H3N2) viruses are currently evolving faster than any other subtype of seasonal influenza. As a result, vaccine efficacy can vary widely from one year to the next, and the wild-type antigens in the seasonal vaccine need to be updated frequently to stay current with the ever-changing viral landscape. To address this, 5 computationally optimized broadly reactive antigens (COBRAs) were designed from influenza A(H3N2) viruses that circulated during 2018 to 2022. These novel vaccine antigens incorporate important immunological epitopes from recently circulating viruses into one vaccine antigen providing the immune system with a variety of targets to elicit protective immune responses against. These computationally optimized H3 hemagglutinin vaccine antigens were first tested in immunologically naïve mice, in which they elicited antibodies with protective hemagglutination inhibition titers and neutralization activity against A(H3N2) vaccine strains from the last decade. Immune responses elicited by these vaccines were further enhanced in cohorts of mice and ferrets that were previously exposed to historical seasonal influenza viruses. In these animals, the COBRA HA antigens recalled epitopes recognized by influenza hemagglutinin-specific memory cells leading to stronger humoral immune responses. Incorporating these antigens into seasonal vaccines could improve protective efficacy in vaccinated individuals and reduce the need to reformulate vaccines annually.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119840","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

Zebrafish fkbp5 attenuates antiviral innate immunity by autophagic degradation of transcription factor irf7. 斑马鱼fkbp5通过转录因子irf7的自噬降解减弱抗病毒先天免疫。

IF 3.6 3区医学

Journal of immunology Pub Date : 2025-05-20 DOI: 10.1093/jimmun/vkaf089

Yanyi Wang, Zhi Li, Ziyi Li, Yanan Song, Jun Li, Le Yuan, Chunling Wang, Fuxiang Lai, Runkun Yan, Wuhan Xiao, Jing Wang

{"title":"Zebrafish fkbp5 attenuates antiviral innate immunity by autophagic degradation of transcription factor irf7.","authors":"Yanyi Wang, Zhi Li, Ziyi Li, Yanan Song, Jun Li, Le Yuan, Chunling Wang, Fuxiang Lai, Runkun Yan, Wuhan Xiao, Jing Wang","doi":"10.1093/jimmun/vkaf089","DOIUrl":"https://doi.org/10.1093/jimmun/vkaf089","url":null,"abstract":"Activation of the type I interferon (IFN-I) signaling pathway is crucial for protecting host cells against viral infections. IFN-I production requires the transcription factors IFN regulatory factor 3 (IRF3) and IRF7, and its regulation must be finely tuned to both combat infection effectively and prevent excessive immunopathology. Here, we report that selective autophagy mediated by zebrafish FK506-binding protein 5 (Fkbp5), a PPIase (peptidyl-prolyl isomerase) promotes the degradation of Irf7 and Irf3, thereby inhibiting virus-induced type I IFN production. Quantitative real-time reverse-transcription polymerase chain reaction experiments indicate that zebrafish fkbp5 is induced by viral infection. Moreover, disrupting fkbp5 in AB-line zebrafish using CRISPR/Cas9 enhances survival rates and reduces viral messenger RNA levels compared with wild-type zebrafish. In cell culture, using promoter analysis and quantitative real-time reverse-transcription polymerase chain reaction, we found fkbp5 overexpression significantly attenuates cellular antiviral capacity and facilitates viral proliferation. Mechanistically, we found that fkbp5 inhibits Irf3/7-induced IFN activation, which depends on the binding of Fkbp5 to the Irf3 or IRF association domain of Irf7 via co-immunoprecipitation and Western blot assays. Furthermore, Fkbp5 induces the autophagic degradation of Irf3 and Irf7 independent of its PPIase activity. Blocking autophagy in vivo and in vitro restores the regulation of the RLR (RIG-I-like receptor) pathway by fkbp5. These findings reveal a critical role for zebrafish fkbp5 in suppressing the activation of Irf7 and Irf3 for IFN signaling and antiviral immune responses.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101819","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