Journal of immunology最新文献_第5页

Delivery of extracellular vesicle-associated microRNA-146a regulates human monocyte phenotype and function. 细胞外囊泡相关microRNA-146a的递送调节人类单核细胞表型和功能。

IF 4 3区医学

Journal of immunology Pub Date : 2026-08-04 DOI: 10.1093/jimmun/vkag226

Kyle I Mentkowski, Touba Tarvirdizadeh, Rohan Pandey, Paul J Schiffmacher, Sara Hough, Lisa A Eagler, Fraser J Sim, Jessica Reynolds, Jennifer K Lang

{"title":"Delivery of extracellular vesicle-associated microRNA-146a regulates human monocyte phenotype and function.","authors":"Kyle I Mentkowski, Touba Tarvirdizadeh, Rohan Pandey, Paul J Schiffmacher, Sara Hough, Lisa A Eagler, Fraser J Sim, Jessica Reynolds, Jennifer K Lang","doi":"10.1093/jimmun/vkag226","DOIUrl":"https://doi.org/10.1093/jimmun/vkag226","url":null,"abstract":"CCR2+ monocytes are recruited to sites of acute myocardial injury, where they play a critical role in clearing necrotic debris and replenishing the depleted resident macrophage population. Although this response is necessary for early tissue repair, prolonged activation of inflammatory pathways and persistent recruitment of CCR2+ monocytes have been associated with accelerated ventricular remodeling and adverse outcomes. Inhibition of CCR2 has shown promise in preclinical models of myocardial injury and represents a potential therapeutic target. Cardiosphere-derived cell extracellular vesicles (CDC-EVs) have demonstrated cardioprotective effects partly through modulation of the immune response. We investigated whether CDC-EVs regulate inflammatory monocyte trafficking through effects on CCR2 signaling. We found that CDC-EVs reduce the surface availability of CCR2 on human monocytes through an miR-146a-dependent mechanism, resulting in decreased monocyte migration toward CCL2. These findings identify a previously unrecognized mechanism by which CDC-EVs modulate CCR2-dependent monocyte trafficking and provide new insight into how EVs regulate innate immune responses after myocardial injury.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689264","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

Isotype-specific antibody secreting plasma cells harbor epigenetic and transcription factor architectures defining distinct cell lineages. 同型特异性抗体分泌浆细胞具有表观遗传和转录因子结构，定义不同的细胞系。

IF 4 3区医学

Journal of immunology Pub Date : 2026-08-04 DOI: 10.1093/jimmun/vkag231

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

{"title":"Isotype-specific antibody secreting plasma cells harbor epigenetic and transcription factor architectures defining distinct cell lineages.","authors":"Lou-Ella M M George-Alexander, Roshni Roy, Sakeenah L Hicks, Mansi Gupta, Christopher D Scharer, Jeremy M Boss","doi":"10.1093/jimmun/vkag231","DOIUrl":"https://doi.org/10.1093/jimmun/vkag231","url":null,"abstract":"Antibody-secreting cells (ASCs) are critical effectors of humoral immunity, wherein their distinct isotypes play specialized roles in pathogen defense. Despite studies defining the transcriptional programs of selected ASC isotypes, specific mechanisms underlying isotype-specific gene regulation are largely unaddressed. Here, we performed an integrated multiomics analysis (RNA sequencing, ATAC-seq [assay for transposase-accessible chromatin using sequencing], DNA methylation) on surface-sorted IgM, IgG, and IgA ASCs isolated from the spleens and mediastinal lymph nodes of mice following influenza infection. Although conclusions regarding temporal and spatial specific programs could not be determined, we observed isotype-enriched expression patterns mapping to TLR signaling, cell cycle, cholesterol metabolism, cell adhesion, and homing. ETS:IRF, NFAT, REL, RUNX, SMAD, and STAT5 binding motifs differentially mapped to isotype-enriched gene expression programs. Additionally, DNA hypomethylation patterns in class-switched ASCs correlate with transcription factor-specific programming. The unique transcriptional and epigenetic programs among the 3 ASC isotypes suggest that each is a distinct lineage that dictates isotype-specific functional characteristics important for humoral immunity.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13480711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794048","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

Immunotherapy of malignant melanoma using T cell-activating microbeads. T细胞活化微珠对恶性黑色素瘤的免疫治疗。

IF 4 3区医学

Journal of immunology Pub Date : 2026-08-04 DOI: 10.1093/jimmun/vkag191

Nada T Hassan, Jessica Löffler, Annika Sachs Dos Santos, Jonas Wohlfarth, Maximiliane Wußmann, Linda Schellhammer, Johannes Vom Berg, Florian Groeber-Becker, Thomas Kerkau, Bastian Schilling, Niklas Beyersdorf

{"title":"Immunotherapy of malignant melanoma using T cell-activating microbeads.","authors":"Nada T Hassan, Jessica Löffler, Annika Sachs Dos Santos, Jonas Wohlfarth, Maximiliane Wußmann, Linda Schellhammer, Johannes Vom Berg, Florian Groeber-Becker, Thomas Kerkau, Bastian Schilling, Niklas Beyersdorf","doi":"10.1093/jimmun/vkag191","DOIUrl":"https://doi.org/10.1093/jimmun/vkag191","url":null,"abstract":"Metastatic disease is the prime cause of death from many malignancies. Due to the multiple different lesions and the increased aggressiveness of the cancer cells, metastatic disease is often difficult to treat. Here, the introduction of immune checkpoint blockers (ICBs) has greatly helped to improve patients' prognosis by harnessing antitumor immunity, particularly anticancer T cells in multiple human cancers. Despite the success of ICBs in, for example, metastatic melanoma 2 major challenges remain in the field: therapy-limiting toxicities induced by systemic ICB administration and lack of a life-prolonging response in a substantial number of patients. Therefore, highly potent local immunotherapeutic approaches might offer a solution and enhance treatment of metastatic disease. Here, we describe antibody-functionalized paramagnetic microbeads as a means to fill this void. These microbeads are readily engulfed by the vast majority of human cancer cell line cells studied inducing direct cytotoxicity (first hit). Focusing on malignant melanoma, we further observed that loading the microbeads with a conventional anti-CD28 monoclonal antibody (bead-bound conventional anti-CD28 monoclonal antibody, BBC-28) not only efficiently induced proliferation and cytokine release by human T cells expressing CD28, but also enhanced killing of melanoma cells by melanoma-reactive T cells (second hit). Thus, we provide proof-of-concept data that BBC-28, after local application into, for example, skin metastases, may also induce a combination of direct toxicity and enhanced anticancer immunity, leading to efficient treatment of metastatic disease.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794055","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

KDM4A promotes microglial pyroptosis and neuropathic pain via the MEG3/SMURF2/HES1 axis. KDM4A通过MEG3/SMURF2/HES1轴促进小胶质细胞焦亡和神经性疼痛。

IF 4 3区医学

Journal of immunology Pub Date : 2026-08-04 DOI: 10.1093/jimmun/vkag223

Na Wang, Shihua Yu, Lixia Chen, Jinlong Yang, Yujie Kou, Xuesong Sun

{"title":"KDM4A promotes microglial pyroptosis and neuropathic pain via the MEG3/SMURF2/HES1 axis.","authors":"Na Wang, Shihua Yu, Lixia Chen, Jinlong Yang, Yujie Kou, Xuesong Sun","doi":"10.1093/jimmun/vkag223","DOIUrl":"https://doi.org/10.1093/jimmun/vkag223","url":null,"abstract":"Neuropathic pain (NP) is a refractory clinical disorder in which microglial pyroptosis plays a crucial role, yet the epigenetic regulation by lysine demethylase 4A (KDM4A) remains unclear. In this study, chronic constriction injury (CCI) rat models were established, and KDM4A was knocked down to evaluate its effects on paw withdrawal mechanical threshold (PWMT), paw withdrawal thermal latency (PWTL), histopathological changes, and NLR family pyrin domain containing 3 (NLRP3)/ionized calcium-binding adapter molecule 1 (Iba1) expression. In vitro, lipopolysaccharide (LPS)-treated BV2 microglial cells were used as an inflammatory model. We found that KDM4A and the long non-coding RNA maternally expressed gene 3 (MEG3) were highly expressed in NP rats. KDM4A inhibition ameliorated CCI-induced symptoms and suppressed microglial pyroptosis in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assays revealed that KDM4A promoted MEG3 expression by removing histone H3 lysine 9 di-/trimethylation (H3K9me2/3) modifications at the MEG3 promoter. RNA immunoprecipitation (RIP) and co-immunoprecipitation (Co-IP) assays further demonstrated that MEG3 at least partially recruited the E3 ubiquitin ligase SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) to bind hairy and enhancer of split 1 (HES1), promoting HES1 ubiquitination and degradation. Rescue experiments confirmed that overexpression of MEG3 or SMURF2 partially reversed the inhibitory effect of KDM4A knockdown on microglial pyroptosis in vitro. In conclusion, KDM4A facilitates microglial pyroptosis and aggravates pain responses in NP rats through the MEG3/SMURF2/HES1 axis in a manner at least partially dependent on SMURF2, providing novel insights into the epigenetic regulation of NP.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794120","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

Unveiling the role of lysosomes in antigen processing and presentation. 揭示溶酶体在抗原加工和递呈中的作用。

IF 4 3区医学

Journal of immunology Pub Date : 2026-08-04 DOI: 10.1093/jimmun/vkag200

Gabriele Sergio Colangelo, Kyra J Cowan, Federico Riccardi Sirtori, Luca Maria Barbero

{"title":"Unveiling the role of lysosomes in antigen processing and presentation.","authors":"Gabriele Sergio Colangelo, Kyra J Cowan, Federico Riccardi Sirtori, Luca Maria Barbero","doi":"10.1093/jimmun/vkag200","DOIUrl":"10.1093/jimmun/vkag200","url":null,"abstract":"Lysosomes drive antigen proteolysis and peptide loading for major histocompatibility complex class II (MHCII) presentation in antigen-presenting cells (APCs), enabling activation of peptide-specific CD4+ T helper cells (CD4+ Th cells). Tight regulation of endocytic trafficking, protease activity, and peptide editing is required to generate stable peptide-MHCII complexes and balanced immune responses. Conversely, dysregulation of antigen catabolism or loading can promote impaired pathological immunity, including autoimmunity. However, key mechanistic questions remain, including how proteolysis, redox regulation, and peptide editing shape the MHCII ligandome across APC subsets and inflammatory states. In this review, we explore the main mechanisms of antigen acquisition, endocytic/lysosomal factors controlling MHCII-restricted processing and presentation, and evidence linking lysosomal dysfunction to autoimmunity. Understanding the functions of lysosomes in immune cells is crucial for elucidating their roles in physiological and pathological states, for developing targeted therapeutic strategies and for enhancing the safety and efficacy of novel biological entities (NBEs).","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148726257","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

Semaphorin3E is a novel regulator of germinal center responses in a mouse model of allergic asthma. 在小鼠过敏性哮喘模型中，Semaphorin3E是一种新的生发中心反应调节因子。

IF 4 3区医学

Journal of immunology Pub Date : 2026-08-04 DOI: 10.1093/jimmun/vkag220

Fatemeh Sedaghat, Mojdeh Matloubi, Lianyu Shan, Chukwunonso Onyilagha, Abdelilah S Gounni

{"title":"Semaphorin3E is a novel regulator of germinal center responses in a mouse model of allergic asthma.","authors":"Fatemeh Sedaghat, Mojdeh Matloubi, Lianyu Shan, Chukwunonso Onyilagha, Abdelilah S Gounni","doi":"10.1093/jimmun/vkag220","DOIUrl":"https://doi.org/10.1093/jimmun/vkag220","url":null,"abstract":"Little is known about the role of semaphorin 3E (Sema3E) in B cell responses and immunoglobulin regulation. Our recent data indicate that Sema3e knockout mice have significantly higher serum levels of total and allergen-specific IgE in allergic asthma, suggesting Sema3E's crucial role in modulating the humoral response. We hypothesized that Sema3E may negatively regulate key T-dependent B cell processes, including germinal center (GC) responses and IgE production. To test this, Sema3e-/- and wild-type C57BL/6 mice underwent the acute house dust mite challenge protocol. We quantified GC B cells, T follicular helper (Tfh) cells, antibody-secreting cells (ASCs), IgE+ B cells, antibody isotypes (IgE, IgG1), and cytokines at baseline and upon allergen airway challenge. GC formation was blocked by intraperitoneal administration of anti-ICOS-L or rat IgG as an isotype control. At the steady state, Sema3e-/- mice had a significantly higher baseline number of GC B cells, Tfh cells, ASCs, and serum IgE compared with the wild-type counterparts. Upon house dust mite immunization, Sema3e-/- mice exhibited enhanced GC responses, IgE production, and B cell costimulatory molecules expression. Interestingly, Sema3E absence in mice led to an increase in the expression of ICOS on CD4+ T cells and disruption of ICOS/ICOS-L signaling, remarkably reducing the number of GC B cells, Tfh cells, IgE+ B cells, ASCs, serum levels of immunoglobulins, and lung inflammatory cells. Collectively, Sema3E may negatively regulate both enhanced GC responses and elevated IgE production at both steady state and postimmunization, highlighting its critical role in controlling humoral immunity and allergic inflammation.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758646","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

Invariant chain controls HLA-DQ folding and shapes the HLA class II proxiome. 不变量链控制HLA- dq折叠并形成HLA II类近体。

IF 4 3区医学

Journal of immunology Pub Date : 2026-08-04 DOI: 10.1093/jimmun/vkag201

Mohamed Abdelwafi Moulefera, William Mitchell, Nabil El Bilali, Abdelilah Majdoubi, Rebecca Panès, Suzanne Salti, Roger Lippé, Étienne Gagnon, Walid Mourad, Jacques Thibodeau

{"title":"Invariant chain controls HLA-DQ folding and shapes the HLA class II proxiome.","authors":"Mohamed Abdelwafi Moulefera, William Mitchell, Nabil El Bilali, Abdelilah Majdoubi, Rebecca Panès, Suzanne Salti, Roger Lippé, Étienne Gagnon, Walid Mourad, Jacques Thibodeau","doi":"10.1093/jimmun/vkag201","DOIUrl":"https://doi.org/10.1093/jimmun/vkag201","url":null,"abstract":"The invariant chain (Ii) trimerizes in the endoplasmic reticulum and swiftly associates with nascent alpha and beta chains of major histocompatibility complex class II (MHCII) molecules. Ii was ascribed many roles pertaining to the antigen presentation capacity of MHCII molecules. The lack of Ii in knockout mice revealed its isotype- and cell type-dependent impact over the folding and trafficking of MHCII molecules. In humans, the role of Ii was mainly assessed in transfected cells. Here, using the CRISPR-Cas9 system, we addressed the impact of inactivating the Ii genes on the expression and functions of MHCII molecules in human B cell lines. Our results revealed that the absence of Ii had very little impact, at least quantitatively, on the surface display of multiple HLA-DR and HLA-DP allotypes. However, Ii had a strong influence on the folding of the many HLA-DQ allotypes expressed in Raji and LG2 cells. Both the p33 and p35 isoforms of Ii could independently restore HLA-DQ expression at the plasma membrane. The loss of Ii did not prevent the presentation of the HA307-318 peptide from the inactivated influenza X31 virus, in line with the fact that this epitope is loaded onto recycling HLA-DR molecules. We also found that Ii reduces the expression of LFA-1, a function that is most likely related to the ability of its cytoplasmic domain to act as a transcriptional regulator. Finally, using a biotin ligation assay in vivo, we identified Ii-dependent proximity partners of the HLA-DRβ cytoplasmic tail. Altogether, these results highlighted the pleiotropic functions of Ii in humans and uncovered new actors involved in the antigen presentation function of MHCII molecules.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794113","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

Deficiency in circulating T cells in four core genotypes mice with Sry translocation. 四种核心基因型Sry易位小鼠循环T细胞缺乏。

IF 4 3区医学

Journal of immunology Pub Date : 2026-08-04 DOI: 10.1093/jimmun/vkag207

Kaitlin E McKernan, Jacqueline-Yvonne Cephus, Shelby N Kuehnle, Emely Henriquez-Pilier, Aamina C Dandy, Tess Bacharier, Vasiliy V Polosukhin, Katherine N Cahill, Patricia Silveyra, Dawn C Newcomb

{"title":"Deficiency in circulating T cells in four core genotypes mice with Sry translocation.","authors":"Kaitlin E McKernan, Jacqueline-Yvonne Cephus, Shelby N Kuehnle, Emely Henriquez-Pilier, Aamina C Dandy, Tess Bacharier, Vasiliy V Polosukhin, Katherine N Cahill, Patricia Silveyra, Dawn C Newcomb","doi":"10.1093/jimmun/vkag207","DOIUrl":"https://doi.org/10.1093/jimmun/vkag207","url":null,"abstract":"Sex differences exist in the immune responses to infections and in the prevalence and severity of autoimmune and allergic diseases. These sex differences may be caused by sex hormones and/or variable inactivation of X chromosome genes. The 4 core genotypes mice allow for distinction between the effects of sex hormones and chromosomes on physiology and disease pathology. In the FCG mouse model, the Sry gene is deleted from the Y chromosome and inserted into chromosome 3 as multiple copies of a transgene, allowing for phenotypic male and female mice with XX and XY chromosomes. We sought to investigate the role of sex hormones and chromosomes in respiratory syncytial virus infection and allergen-induced airway inflammation. However, in performing these studies, we found that the immune response in FCG males (XXM and XYM) was significantly blunted. XXF and XYF had 4-fold more CD3+CD4+ T cells and over 7-fold more CD3+CD8+ T cells compared to XXM and XYM in the lungs following stimulus. CD4+ and CD8+ T cells were also significantly decreased in XXM and XYM mice in the lungs, spleen, and peripheral blood at baseline with no effect on B cells, NK cells, or myeloid cells. Thymic T cell numbers were similar among groups, and bone marrow progenitors were unchanged between groups. Overall, the translocation of Sry to chromosome 3 resulted in dramatically decreased immune responses to RSV infection and allergen-challenge, indicating that FCG male mice do not mount appropriate immune responses to a respiratory virus infection.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13472664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148766460","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

Recombinant SpTrf proteins illustrate putative functions of native SpTrf proteins: from immune response to resolution in sea urchins. 重组SpTrf蛋白说明了天然SpTrf蛋白的推测功能：从免疫反应到海胆的溶解。

IF 4 3区医学

Journal of immunology Pub Date : 2026-08-04 DOI: 10.1093/jimmun/vkag213

Ryley S Crow, Christopher Grubb, Joseph W Meisel, L Courtney Smith

{"title":"Recombinant SpTrf proteins illustrate putative functions of native SpTrf proteins: from immune response to resolution in sea urchins.","authors":"Ryley S Crow, Christopher Grubb, Joseph W Meisel, L Courtney Smith","doi":"10.1093/jimmun/vkag213","DOIUrl":"https://doi.org/10.1093/jimmun/vkag213","url":null,"abstract":"The complex and sophisticated sea urchin innate immune system relies on conserved immune receptor and effector molecules plus the euechinoid-specific Transformer family. Native SpTransformer (natSpTrf) proteins in Strongylocentrotus purpuratus respond to immune challenge by augmenting phagocytosis of microbes. These proteins show significant sequence diversity both within and among sea urchins with the predicted benefit of host protection through the recognition of a broad range of pathogens. Prior reports show that 6 recombinant (r)SpTrf proteins from insect cells induce phagocytosis when cross-linked to inert beads. Soluble rSpTrf proteins bind phagocytes, which respond by downregulating expression of the SpTrf gene family and SpIL17-9. Here we extend this analysis to determine the rSpTrf protein binding targets and find that they fail to bind pathogen-associated molecular patterns (PAMPs) and bacteria. Similarly, Ni-isolated natSpTrf proteins also fail to bind the same PAMPs. The insect cells add posttranslational modifications to the rSpTrf proteins that impart protein stability and impact predicted structure. Together with prior results, our findings suggest a working hypothesis for the natSpTrf proteins in vivo in which disordered natSpTrf proteins bind to pathogens, transform to secondary structure, and augment phagocytosis leading to pathogen clearance. Upon pathogen clearance, unbound natSpTrf proteins transform, multimerize, and bind to phagocytes. The cellular response adjusts expression of the SpTrf genes and SpIL17-9 to the threat level. This hypothesis suggests that the natSpTrf proteins participate in immune responses to foreign challenge but also function in immune resolution after pathogen clearance.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794036","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

ACE2 decoy Fc-fusions and bispecific killer engagers require Fc engagement for in vivo efficacy against SARS-CoV-2. ACE2诱饵Fc融合体和双特异性杀伤接合体需要Fc接合才能在体内有效对抗SARS-CoV-2。

IF 4 3区医学

Journal of immunology Pub Date : 2026-08-04 DOI: 10.1093/jimmun/vkag235

Jenna K Dick, Venkatramana D Krishna, Dustin Hicks, Jules A Sangala, Robert J Oldham, Benjamin T Zandstra, Carly Baehr, J Sjef Verbeek, Mark S Cragg, Marco Pravetoni, Maxim C-J Cheeran, Geoffrey T Hart

{"title":"ACE2 decoy Fc-fusions and bispecific killer engagers require Fc engagement for in vivo efficacy against SARS-CoV-2.","authors":"Jenna K Dick, Venkatramana D Krishna, Dustin Hicks, Jules A Sangala, Robert J Oldham, Benjamin T Zandstra, Carly Baehr, J Sjef Verbeek, Mark S Cragg, Marco Pravetoni, Maxim C-J Cheeran, Geoffrey T Hart","doi":"10.1093/jimmun/vkag235","DOIUrl":"10.1093/jimmun/vkag235","url":null,"abstract":"SARS-CoV-2 has continued to evolve over time, necessitating the adaptation of vaccines to maintain efficacy. Monoclonal antibodies (mAbs) against SARS-CoV-2 were a key line of defense for unvaccinated or immunocompromised individuals. However, these mAbs are now ineffective against current SARS-CoV-2 variants. Here, we tested 3 aspects of αSARS-CoV-2 therapeutics. First, we tested whether Fc engagement is necessary for in vivo clearance of SARS-CoV-2. Second, we tested bispecific killer engagers (BiKEs) that simultaneously engage SARS-CoV-2 and a specific Fc receptor. Benefits of these engagers include the ease of manufacturing, stability, more cell-specific targeting, and high affinity binding to Fc receptors. Using both mAbs and BiKEs, we found that both neutralization and Fc receptor engagement were necessary for effective SARS-CoV-2 clearance. Third, due to ACE2 being necessary for viral entry, ACE2 will maintain binding to SARS-CoV-2 despite viral evolution. Therefore, we used an ACE2 decoy Fc-fusion or BiKE, instead of an αSARS-CoV-2 antibody sequence, as a potential therapeutic that would withstand viral evolution. We found that the ACE2 decoy approach also required Fc receptor engagement and, unlike traditional neutralizing antibodies against specific variants, enabled the clearance of two distinct SARS-CoV-2 variants. These data show the importance of Fc engagement for mAbs, the utility of BiKEs as therapies for infectious disease, and the in vivo effectiveness of the ACE2 decoy approach. With further studies, we predict that combining neutralization, the cellular response, and this ACE2 decoy approach will benefit individuals with ineffective antibody levels.","PeriodicalId":16045,"journal":{"name":"Journal of immunology","volume":"215 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13500110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808616","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