Pub Date : 2024-09-13DOI: 10.1101/2024.09.08.611931
Joseph J. Zeppa, Jamie E. Fegan, Pauline Maiello, Epshita A. Islam, Isaac S. Lee, Christine Pham, Laura-Lee Caruso, Scott D. Gray-Owen
Retrospective epidemiological studies suggest that the licensed serogroup B meningococcal vaccine 4CMenB (Bexsero) provides some protection against the closely related pathogen Neisseria gonorrhoeae in humans. This result has been replicated in murine models of gonococcal colonization, with a gonococci-reactive humoral response and more rapid clearance of vaginal infection. However, immunization with Bexsero consistently elicits a robust humoral response but does not protect all individuals, so the correlates of protection remain undefined. Herein, we exploit the fact that Bexsero promotes clearance in only a subset of immunized mice to perform a broad analysis of the adaptive response in animals that are or are not protected. We observe that Bexsero vaccination induces high levels of anti-neisserial antibodies in both serum and the vaginal lumen, and a robust cellular response highlighted by an increase in both conventional naive and memory populations as well as unconventional lymphocyte subsets. Multiplex and flow cytometry results show that Bexsero vaccination generates a robust, multi-faceted cytokine response that spans numerous T cell subsets (TH1, TH2, Treg and TH17 responses) and that non-T non-B lymphocytes play an important role in this response, as indicated by an unbiased principal component analysis. Together, this work provides the first comprehensive analysis of the robust humoral and complex cellular response to Bexsero so as to reveal the effector mechanisms that may contribute to immunity against vaginal gonococcal infection.
回顾性流行病学研究表明，获得许可的血清 B 群脑膜炎球菌疫苗 4CMenB（Bexsero）对人类密切相关的病原体淋病奈瑟菌有一定的保护作用。这一结果在淋球菌定植的小鼠模型中得到了复制，出现了淋球菌反应性体液反应，阴道感染清除得更快。然而，用 Bexsero 免疫接种可持续引起强大的体液反应，但并不能保护所有个体，因此保护的相关因素仍未确定。在本文中，我们利用 Bexsero 只对免疫小鼠中的一部分产生清除作用这一事实，对受到或未受到保护的动物的适应性反应进行了广泛分析。我们观察到，Bexsero 疫苗接种能在血清和阴道腔中诱导出高水平的抗奈瑟氏菌抗体，并诱导出强大的细胞反应，突出表现为传统的幼稚群和记忆群以及非常规淋巴细胞亚群的增加。多重和流式细胞术结果表明，Bexsero 疫苗接种会产生强大的、多方面的细胞因子反应，跨越多个 T 细胞亚群（TH1、TH2、Treg 和 TH17 反应），而且非 T 非 B 淋巴细胞在这种反应中发挥了重要作用，无偏主成分分析表明了这一点。总之，这项研究首次全面分析了对贝克斯罗的强大体液和复杂细胞反应，从而揭示了可能有助于抵抗阴道淋球菌感染的效应机制。
{"title":"Meningococcal vaccine Bexsero elicits a robust cellular immune response that targets but is not consistently protective against Neisseria gonorrhoeae during murine vaginal infection","authors":"Joseph J. Zeppa, Jamie E. Fegan, Pauline Maiello, Epshita A. Islam, Isaac S. Lee, Christine Pham, Laura-Lee Caruso, Scott D. Gray-Owen","doi":"10.1101/2024.09.08.611931","DOIUrl":"https://doi.org/10.1101/2024.09.08.611931","url":null,"abstract":"Retrospective epidemiological studies suggest that the licensed serogroup B meningococcal vaccine 4CMenB (Bexsero) provides some protection against the closely related pathogen Neisseria gonorrhoeae in humans. This result has been replicated in murine models of gonococcal colonization, with a gonococci-reactive humoral response and more rapid clearance of vaginal infection. However, immunization with Bexsero consistently elicits a robust humoral response but does not protect all individuals, so the correlates of protection remain undefined. Herein, we exploit the fact that Bexsero promotes clearance in only a subset of immunized mice to perform a broad analysis of the adaptive response in animals that are or are not protected. We observe that Bexsero vaccination induces high levels of anti-neisserial antibodies in both serum and the vaginal lumen, and a robust cellular response highlighted by an increase in both conventional naive and memory populations as well as unconventional lymphocyte subsets. Multiplex and flow cytometry results show that Bexsero vaccination generates a robust, multi-faceted cytokine response that spans numerous T cell subsets (TH1, TH2, Treg and TH17 responses) and that non-T non-B lymphocytes play an important role in this response, as indicated by an unbiased principal component analysis. Together, this work provides the first comprehensive analysis of the robust humoral and complex cellular response to Bexsero so as to reveal the effector mechanisms that may contribute to immunity against vaginal gonococcal infection.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.08.611916
Leonard Angka, Gayashan Tennakoon, David P Cook, Andre B Martel, Marisa R Market, Christiano Tanese de Souza, Emma Cummins, Ismael Samudio, Natasha Kekre, Michele Ardolino, Barbara Vanderhyden, Michael A Kennedy, Rebecca C Auer
Myeloid derived suppressor cells (MDSCs) have a dominating presence in the postoperative period and mediate the suppression of Natural Killer (NK) cells and promotion of cancer metastases after surgery. However, their functional characteristics and effect on cellular immunity after surgery have not been comprehensively investigated. Here, we characterize the expansion of surgery-induced (sx) MDSCs via multi-colour flow cytometry, single-cell RNA sequencing, and functional ex vivo NK cell suppression assays. We then screened a small molecule library using our sx-MDSC:NK cell suppression assay to identify compounds that could inhibit sx-MDSCs. These studies provide evidence that PI3K-γ signalling is upregulated in sx-MDSCs and blockade with PI3K-γ specific inhibitors attenuates NK cell suppression in humans and mice and reduces postoperative metastases in murine models. Upregulated PI3K-γ in sx-MDSCs is a potential pathway amenable to therapeutic targeting in the postoperative period.
髓系衍生抑制细胞（MDSCs）在术后占主导地位，并在术后介导抑制自然杀伤细胞（NK）和促进癌症转移。然而，它们的功能特点及其对术后细胞免疫的影响尚未得到全面研究。在这里，我们通过多色流式细胞术、单细胞 RNA 测序和体内外 NK 细胞抑制功能测试，描述了手术诱导（sx）MDSCs 的扩增特征。然后，我们利用我们的sx-MDSC:NK细胞抑制实验筛选了一个小分子库，以确定能抑制sx-MDSCs的化合物。这些研究提供的证据表明，PI3K-γ 信号在 sx-MDSCs 中上调，使用 PI3K-γ 特异性抑制剂阻断 PI3K-γ 信号可减轻人和小鼠的 NK 细胞抑制，并减少小鼠模型的术后转移。sx-MDSCs中上调的PI3K-γ是一种潜在的途径，可用于术后靶向治疗。
{"title":"Preventing surgery induced immune suppression and metastases by inhibiting PI3K-gamma signalling in Myeloid-Derived Suppressor Cells.","authors":"Leonard Angka, Gayashan Tennakoon, David P Cook, Andre B Martel, Marisa R Market, Christiano Tanese de Souza, Emma Cummins, Ismael Samudio, Natasha Kekre, Michele Ardolino, Barbara Vanderhyden, Michael A Kennedy, Rebecca C Auer","doi":"10.1101/2024.09.08.611916","DOIUrl":"https://doi.org/10.1101/2024.09.08.611916","url":null,"abstract":"Myeloid derived suppressor cells (MDSCs) have a dominating presence in the postoperative period and mediate the suppression of Natural Killer (NK) cells and promotion of cancer metastases after surgery. However, their functional characteristics and effect on cellular immunity after surgery have not been comprehensively investigated. Here, we characterize the expansion of surgery-induced (sx) MDSCs via multi-colour flow cytometry, single-cell RNA sequencing, and functional ex vivo NK cell suppression assays. We then screened a small molecule library using our sx-MDSC:NK cell suppression assay to identify compounds that could inhibit sx-MDSCs. These studies provide evidence that PI3K-γ signalling is upregulated in sx-MDSCs and blockade with PI3K-γ specific inhibitors attenuates NK cell suppression in humans and mice and reduces postoperative metastases in murine models. Upregulated PI3K-γ in sx-MDSCs is a potential pathway amenable to therapeutic targeting in the postoperative period.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.12.612662
Susanna E Barouch, Kate S Levine, Ross Blanc, Qixin Wang, Xin Tong, Ryan P McNamara
In the fall of 2023, the monovalent XBB.1.5 mRNA vaccine for COVID-19 became available. However, the comparative magnitude, durability, and functionality of antibody responses induced by the XBB.1.5 vaccine compared with the 2022-2023 bivalent wildtype (WT) + Omicron BA.5 vaccine remains to be fully determined. In this study, we compared antibody profiles generated by these two vaccines in healthcare workers. We show that the monovalent XBB.1.5 vaccine induced higher magnitude binding, neutralizing, and Fc-gamma receptor (FcγR) binding antibodies to the XBB.1.5 spike compared with the bivalent vaccine against the WT and BA.5 spikes, both at both peak immunogenicity and at 6 months post-vaccination. Moreover, antibody interaction architectures and correlations remained more robust at 6 months post-vaccination with the XBB.1.5 vaccine, whereas these correlations were largely lost at 6 months with the bivalent vaccine. Our results suggest that the XBB.1.5 vaccine led to a more durable and functionally coordinated antibody response compared to the bivalent vaccine.
{"title":"Monovalent XBB.1.5 mRNA Vaccine Recalls a More Durable and Coordinated Antibody Response to SARS-CoV-2 Spike than the Bivalent WT/BA.5 mRNA Vaccine","authors":"Susanna E Barouch, Kate S Levine, Ross Blanc, Qixin Wang, Xin Tong, Ryan P McNamara","doi":"10.1101/2024.09.12.612662","DOIUrl":"https://doi.org/10.1101/2024.09.12.612662","url":null,"abstract":"In the fall of 2023, the monovalent XBB.1.5 mRNA vaccine for COVID-19 became available. However, the comparative magnitude, durability, and functionality of antibody responses induced by the XBB.1.5 vaccine compared with the 2022-2023 bivalent wildtype (WT) + Omicron BA.5 vaccine remains to be fully determined. In this study, we compared antibody profiles generated by these two vaccines in healthcare workers. We show that the monovalent XBB.1.5 vaccine induced higher magnitude binding, neutralizing, and Fc-gamma receptor (FcγR) binding antibodies to the XBB.1.5 spike compared with the bivalent vaccine against the WT and BA.5 spikes, both at both peak immunogenicity and at 6 months post-vaccination. Moreover, antibody interaction architectures and correlations remained more robust at 6 months post-vaccination with the XBB.1.5 vaccine, whereas these correlations were largely lost at 6 months with the bivalent vaccine. Our results suggest that the XBB.1.5 vaccine led to a more durable and functionally coordinated antibody response compared to the bivalent vaccine.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.09.611994
Lien Van Hoecke, Janne Verreycken, Lore Van Acker, Laura Amelinck, Junhua Xie, Jonas Castelein, Elien Van Wonterghem, Griet Van Imschoot, Marlies Burgelman, Sarah Vanherle, Ilse Dewachter, Paulien Baeten, Bieke Broux, Roosmarijn E. Vandenbroucke
In efforts to find reparative strategies for brain damage, brain-associated regulatory T cells (Tregs) have gained increasing attention in recent years. Beyond their textbook immunoregulatory function, Tregs have emerged as key players in the response to brain trauma and the restoration of damaged brain tissue. Here, we are the first to describe a novel, non-canonical function of Tregs in maintaining the sealing capacity of both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Moreover, we identified the cytokine IL-34 as a critical determinant in this newly unveiled Treg function. Mechanistically, IL-34 exerts its influence by modulating the expression and localization of the tight junction protein ZO-1 in both BBB endothelial cells and choroid plexus epithelial cells, thereby reinforcing the strength of the brain barriers. Given the well-established notion of leaky brain barriers and the involvement of immunological components in neurological diseases such as Alzheimer's disease (AD) and multiple sclerosis (MS), we further demonstrate diminished IL-34 expression in Tregs derived from patients with relapsing-remitting MS (RR-MS) and patients with AD and even mild cognitive impairment (MCI). Remarkably, our study reveals the potential of IL-34 treatment in reinstating the integrity of brain barriers within murine models mimicking these neurological disorders. These ground-breaking findings shed light on the intricate relationship between Tregs, IL-34, and the integrity of brain barriers. They offer novel avenues for therapeutic approaches to ameliorate brain barrier dysfunction in the context of neurological disorders.
{"title":"IL-34 empowers regulatory T cells with novel non-canonical function to safeguard brain barrier integrity during neuro-inflammation.","authors":"Lien Van Hoecke, Janne Verreycken, Lore Van Acker, Laura Amelinck, Junhua Xie, Jonas Castelein, Elien Van Wonterghem, Griet Van Imschoot, Marlies Burgelman, Sarah Vanherle, Ilse Dewachter, Paulien Baeten, Bieke Broux, Roosmarijn E. Vandenbroucke","doi":"10.1101/2024.09.09.611994","DOIUrl":"https://doi.org/10.1101/2024.09.09.611994","url":null,"abstract":"In efforts to find reparative strategies for brain damage, brain-associated regulatory T cells (Tregs) have gained increasing attention in recent years. Beyond their textbook immunoregulatory function, Tregs have emerged as key players in the response to brain trauma and the restoration of damaged brain tissue. Here, we are the first to describe a novel, non-canonical function of Tregs in maintaining the sealing capacity of both the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier. Moreover, we identified the cytokine IL-34 as a critical determinant in this newly unveiled Treg function. Mechanistically, IL-34 exerts its influence by modulating the expression and localization of the tight junction protein ZO-1 in both BBB endothelial cells and choroid plexus epithelial cells, thereby reinforcing the strength of the brain barriers. Given the well-established notion of leaky brain barriers and the involvement of immunological components in neurological diseases such as Alzheimer's disease (AD) and multiple sclerosis (MS), we further demonstrate diminished IL-34 expression in Tregs derived from patients with relapsing-remitting MS (RR-MS) and patients with AD and even mild cognitive impairment (MCI). Remarkably, our study reveals the potential of IL-34 treatment in reinstating the integrity of brain barriers within murine models mimicking these neurological disorders. These ground-breaking findings shed light on the intricate relationship between Tregs, IL-34, and the integrity of brain barriers. They offer novel avenues for therapeutic approaches to ameliorate brain barrier dysfunction in the context of neurological disorders.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.03.610972
Alicia Derrac Soria, Myles J Lewis, Xiao Liu, Jason P Twohig, Federica Monaco, Sandra Dimonte, Ana Cardus Figueras, Aisling Morrin, Carol Guy, Benjamin C Cossins, Robert Benson, Robert Andrews, Ernest H Choy, Paul Garside, Muneerah Huwaikem, Marc P Stemmler, Simone Brabletz, Thomas Brabletz, Florian A Siebzehnrubl, Neil Rodrigues, Brendan J Jenkins, Costantino Pitzalis, Gareth W Jones, Simon A Jones
Joint pathology in rheumatoid arthritis is heterogeneous, with histology providing evidence of fibroblast-driven, myeloid-driven, and lymphoid-driven synovitis. However, the immuno-modulatory pathways underlying their development remain unclear. Profiling synovial tissues from rheumatoid arthritis patients and mice with antigen-induced arthritis, we identified a subset of synovial infiltrating CD4+ T-cells expressing CRTAM (class-I MHC-restricted T-cell-associated molecule). In human synovial biopsies, CRTAM correlated with the expression of effector cytokines (IL21, IFNG), chemokine receptors (CXCR3, CXCR4, CCR5), granzymes (GZMA, GZMB, GZMK), and regulatory factors (TIGIT, EOMES, BATF) linked with T-cell-mediated immunity. Studies of antigen-induced arthritis showed that CRTAM+CD4+ T-cells accumulate in the inflamed synovium following disease onset. CRTAM+CD4+ T-cells were particularly abundant in synovial tissue from Il27ra-/- mice displaying ectopic lymphoid-like structures. CADM1 (cell adhesion molecule-1), the endogenous ligand for CRTAM, was also expressed in human synovitis and synovial tissues from wild-type, Il6ra-/-, and Il27ra-/- mice with antigen-induced arthritis. Cells expressing human CADM1 included synovial fibroblasts and subsets of monocytic and CD19+ cells. Considering the ex vivo regulation of CRTAM, we identified that activation of naive CD4+ T-cell increased CRTAM expression. This induction was blocked by IL-6 and IL-27, with further studies identifying a role for STAT3 in controlling the CRTAM transcriptional repressor, ZEB1. These results provide insights into the cytokine control of CRTAM on CD4+ T-cells and support the involvement of CRTAM+CD4+ T-cells in lymphoid-driven synovitis.
类风湿性关节炎的关节病理变化多种多样，组织学显示有成纤维细胞驱动型、髓细胞驱动型和淋巴细胞驱动型滑膜炎。然而，这些滑膜炎发生的免疫调节途径仍不清楚。通过分析类风湿性关节炎患者和抗原诱导关节炎小鼠的滑膜组织，我们发现了一个表达 CRTAM（I 类 MHC 限制性 T 细胞相关分子）的 CD4+ T 细胞浸润滑膜亚群。在人体滑膜活检中，CRTAM 与效应细胞因子（IL21、IFNG）、趋化因子受体（CXCR3、CXCR4、CCR5）、颗粒酶（GZMA、GZMB、GZMK）以及与 T 细胞介导的免疫相关的调节因子（TIGIT、EOMES、BATF）的表达相关。对抗原诱导的关节炎的研究表明，CRTAM+CD4+ T 细胞会在发病后积聚在发炎的滑膜中。在显示异位淋巴样结构的 Il27ra-/- 小鼠滑膜组织中，CRTAM+CD4+ T 细胞尤其丰富。CADM1（细胞粘附分子-1）是CRTAM的内源性配体，在人类滑膜炎以及野生型、Il6ra-/-和Il27ra-/-小鼠抗原诱发关节炎的滑膜组织中也有表达。表达人 CADM1 的细胞包括滑膜成纤维细胞以及单核细胞和 CD19+ 细胞亚群。考虑到 CRTAM 的体内外调控，我们发现激活幼稚 CD4+ T 细胞会增加 CRTAM 的表达。这种诱导作用被 IL-6 和 IL-27 阻断，进一步研究发现 STAT3 在控制 CRTAM 转录抑制因子 ZEB1 中的作用。这些结果为细胞因子控制 CD4+ T 细胞上的 CRTAM 提供了见解，并支持 CRTAM+CD4+ T 细胞参与淋巴驱动的滑膜炎。
{"title":"IL-6 and IL-27 negatively regulate CRTAM-expressing CD4+ T-cells associated with lymphoid-driven synovitis.","authors":"Alicia Derrac Soria, Myles J Lewis, Xiao Liu, Jason P Twohig, Federica Monaco, Sandra Dimonte, Ana Cardus Figueras, Aisling Morrin, Carol Guy, Benjamin C Cossins, Robert Benson, Robert Andrews, Ernest H Choy, Paul Garside, Muneerah Huwaikem, Marc P Stemmler, Simone Brabletz, Thomas Brabletz, Florian A Siebzehnrubl, Neil Rodrigues, Brendan J Jenkins, Costantino Pitzalis, Gareth W Jones, Simon A Jones","doi":"10.1101/2024.09.03.610972","DOIUrl":"https://doi.org/10.1101/2024.09.03.610972","url":null,"abstract":"Joint pathology in rheumatoid arthritis is heterogeneous, with histology providing evidence of fibroblast-driven, myeloid-driven, and lymphoid-driven synovitis. However, the immuno-modulatory pathways underlying their development remain unclear. Profiling synovial tissues from rheumatoid arthritis patients and mice with antigen-induced arthritis, we identified a subset of synovial infiltrating CD4+ T-cells expressing CRTAM (class-I MHC-restricted T-cell-associated molecule). In human synovial biopsies, CRTAM correlated with the expression of effector cytokines (IL21, IFNG), chemokine receptors (CXCR3, CXCR4, CCR5), granzymes (GZMA, GZMB, GZMK), and regulatory factors (TIGIT, EOMES, BATF) linked with T-cell-mediated immunity. Studies of antigen-induced arthritis showed that CRTAM+CD4+ T-cells accumulate in the inflamed synovium following disease onset. CRTAM+CD4+ T-cells were particularly abundant in synovial tissue from Il27ra-/- mice displaying ectopic lymphoid-like structures. CADM1 (cell adhesion molecule-1), the endogenous ligand for CRTAM, was also expressed in human synovitis and synovial tissues from wild-type, Il6ra-/-, and Il27ra-/- mice with antigen-induced arthritis. Cells expressing human CADM1 included synovial fibroblasts and subsets of monocytic and CD19+ cells. Considering the ex vivo regulation of CRTAM, we identified that activation of naive CD4+ T-cell increased CRTAM expression. This induction was blocked by IL-6 and IL-27, with further studies identifying a role for STAT3 in controlling the CRTAM transcriptional repressor, ZEB1. These results provide insights into the cytokine control of CRTAM on CD4+ T-cells and support the involvement of CRTAM+CD4+ T-cells in lymphoid-driven synovitis.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Different memory CD8+ T cell subsets are generated following acute responses: central, effector and resident (Trm). CD8+ Trm cells established residency at the sites of infection and provide an efficient and rapid frontline defense against re-infection. The NR4A family members (NR4A1, NR4A2 and NR4A3) of orphan nuclear receptor are transiently expressed following TCR signaling and NR4As were shown to influence CD8+ T cell response. Interestingly, Nr4a1, Nr4a2 and Nr4a3 have been reported to be transcribed by CD8+ Trm cells. In absence of NR4A1, less CD8+ Trm cells are present in the liver, lungs, small intestine intra-epithelial lymphocytes (IELs) and Peyers patches. NR4A2 was shown to play a role in the generation of small intestine IEL CD8+ Trm cells. However, evidence is still lacking for the contribution of NR4A3 during CD8+ Tm cell differentiation. In this study, we evaluated the role of NR4A3 in the differentiation and maintenance of CD8+ Trm cells. Our data demonstrate that in contrast to the other family members NR4A1 and NR4A2, NR4A3 is dispensable for the generation of CD8+ Trm cells in both epithelial and non-epithelial sites.
{"title":"The orphan nuclear receptor NR4A3 is dispensable for resident memory CD8+ T cell generation","authors":"Livia Odagiu, Salix Boulet, Dave Maurice-De Sousa, Jean-François Daudelin, Nathalie Labrecque","doi":"10.1101/2024.09.09.612076","DOIUrl":"https://doi.org/10.1101/2024.09.09.612076","url":null,"abstract":"Different memory CD8+ T cell subsets are generated following acute responses: central, effector and resident (Trm). CD8+ Trm cells established residency at the sites of infection and provide an efficient and rapid frontline defense against re-infection. The NR4A family members (NR4A1, NR4A2 and NR4A3) of orphan nuclear receptor are transiently expressed following TCR signaling and NR4As were shown to influence CD8+ T cell response. Interestingly, Nr4a1, Nr4a2 and Nr4a3 have been reported to be transcribed by CD8+ Trm cells. In absence of NR4A1, less CD8+ Trm cells are present in the liver, lungs, small intestine intra-epithelial lymphocytes (IELs) and Peyers patches. NR4A2 was shown to play a role in the generation of small intestine IEL CD8+ Trm cells. However, evidence is still lacking for the contribution of NR4A3 during CD8+ Tm cell differentiation. In this study, we evaluated the role of NR4A3 in the differentiation and maintenance of CD8+ Trm cells. Our data demonstrate that in contrast to the other family members NR4A1 and NR4A2, NR4A3 is dispensable for the generation of CD8+ Trm cells in both epithelial and non-epithelial sites.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.08.611873
Nicolas Millet, Jinendiran Sekar, Norma V. Solis, Antoine Millet, Felix E.Y. Aggor, Asia Wildeman, Michail S. Lionakis, Sarah L. Gaffen, Nicholas Jendzjowsky, Scott G. Filler, Marc Swidergall
Mucosal barrier integrity is vital for homeostasis with commensal organisms while preventing pathogen invasion. We unexpectedly found that fungal-induced immunosurveillance enhances resistance to fungal outgrowth and tissue invasion by remodeling the oral mucosal epithelial barrier in mouse models of adult and neonatal Candida albicans colonization. Epithelial subset expansion and tissue remodeling were dependent on interleukin-22 (IL-22) and signal transducer and activator of transcription 3 (STAT3) signaling, through a non-canonical receptor complex composed of glycoprotein 130 (gp130) coupled with IL-22RA1 and IL-10RB. Immunosurveillance-induced epithelial remodeling was restricted to the oral mucosa, whereas barrier architecture was reset once fungal-specific immunity developed. Collectively, these findings identify fungal-induced transient mucosal remodeling as a critical determinant of resistance to mucosal fungal infection during early stages of microbial colonization.
{"title":"Non-canonical IL-22 receptor signaling remodels the mucosal barrier during fungal immunosurveillance","authors":"Nicolas Millet, Jinendiran Sekar, Norma V. Solis, Antoine Millet, Felix E.Y. Aggor, Asia Wildeman, Michail S. Lionakis, Sarah L. Gaffen, Nicholas Jendzjowsky, Scott G. Filler, Marc Swidergall","doi":"10.1101/2024.09.08.611873","DOIUrl":"https://doi.org/10.1101/2024.09.08.611873","url":null,"abstract":"Mucosal barrier integrity is vital for homeostasis with commensal organisms while preventing pathogen invasion. We unexpectedly found that fungal-induced immunosurveillance enhances resistance to fungal outgrowth and tissue invasion by remodeling the oral mucosal epithelial barrier in mouse models of adult and neonatal Candida albicans colonization. Epithelial subset expansion and tissue remodeling were dependent on interleukin-22 (IL-22) and signal transducer and activator of transcription 3 (STAT3) signaling, through a non-canonical receptor complex composed of glycoprotein 130 (gp130) coupled with IL-22RA1 and IL-10RB. Immunosurveillance-induced epithelial remodeling was restricted to the oral mucosa, whereas barrier architecture was reset once fungal-specific immunity developed. Collectively, these findings identify fungal-induced transient mucosal remodeling as a critical determinant of resistance to mucosal fungal infection during early stages of microbial colonization.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Respiratory virus infections are invariably accompanied by an increase in oxidative stress, characterised by elevated production of Reactive Oxygen Species (ROS) in the lung, which plays a pivotal role in both pathogenesis and host defence. Using a mouse model, neutrophil NADPH Oxidase 2 (Nox2) emerges as a key player, primarily responsible for generation of ROS during the early phases of Influenza A Virus (IAV) infection. Neutrophil Nox2-derived ROS display a multifaceted role, not only unleashing oxidative stress but in turn curbing Neutrophil-derived IL-1beta signalling. Absence of neutrophil Nox2 triggered heightened production of IL-1β, promoting the proliferation of IL-17-producing gamma delta (gamma delta) T cells. This early self-amplified augmentation of the IL-beta/IL-17 axis counteracted the antiviral interferon response against IAV infection in mice. We extended our findings to humans. Similar patterns of ROS production and cytokine regulation were observed in human neutrophils when exposed to virus analogue poly(I:C) and SARS-CoV-2. Our discovery highlights that ROS, often associated with harm, play a dual role by regulating cytokine signalling and thus influencing the immune response against respiratory viruses.
{"title":"Neutrophil NADPH oxidase breaks the inflammatory IL-1beta/IL-17A circuit to enhance pathogen clearance during respiratory virus infections.","authors":"Aderonke Sofoluwe, Angelos Petropoulos, Abhilesh Salil Goomanee, Zehra Fatima Ali-Khan, Annika Warnatsch","doi":"10.1101/2024.09.12.612505","DOIUrl":"https://doi.org/10.1101/2024.09.12.612505","url":null,"abstract":"Respiratory virus infections are invariably accompanied by an increase in oxidative stress, characterised by elevated production of Reactive Oxygen Species (ROS) in the lung, which plays a pivotal role in both pathogenesis and host defence. Using a mouse model, neutrophil NADPH Oxidase 2 (Nox2) emerges as a key player, primarily responsible for generation of ROS during the early phases of Influenza A Virus (IAV) infection. Neutrophil Nox2-derived ROS display a multifaceted role, not only unleashing oxidative stress but in turn curbing Neutrophil-derived IL-1beta signalling. Absence of neutrophil Nox2 triggered heightened production of IL-1β, promoting the proliferation of IL-17-producing gamma delta (gamma delta) T cells. This early self-amplified augmentation of the IL-beta/IL-17 axis counteracted the antiviral interferon response against IAV infection in mice. We extended our findings to humans. Similar patterns of ROS production and cytokine regulation were observed in human neutrophils when exposed to virus analogue poly(I:C) and SARS-CoV-2. Our discovery highlights that ROS, often associated with harm, play a dual role by regulating cytokine signalling and thus influencing the immune response against respiratory viruses.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"187 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.08.611874
Jose Marcos Sanches, Rajalakshmy Ayilam Ramachandran, Natalia Mussi, Hamid Baniasadi, Danielle M Robertson
Purpose: As an external mucosal surface, the corneal epithelium is subject to a barrage of stressors that are known to trigger inflammation. IL-1b, a master regulator of inflammation, is secreted into the preocular tear film by ocular surface epithelial cells and infiltrating immune cells. While increased levels of IL-1b have been associated with corneal disease, the effects of IL-1b on mitochondrial function in corneal epithelial cells (CECs) is unknown. Methods: To investigate the effects of IL-1b on mitochondrial function, telomerase immortalized human CECs were cultured in either 50 ng/mL or 100 ng/mL IL-1b for short term (24 hours) or prolonged (72 hours) time periods. Cells were assessed for ROS, inflammatory cytokine production, mitochondrial polarization and ultrastructure, mitophagy, and changes in the metabolite composition. Lipid drops were examined using light and fluorescent microscopy. Results: Short term exposure to IL-1b triggered an increase in IL-8 and ROS levels that corresponded to a reduction in mitochondrial membrane potential. Long term exposure also showed increased levels of IL-8 and IL-6 and further increased ROS. After long term exposure however, there was a paradoxical increase in mitochondrial membrane potential that was associated an increase in spare respiratory capacity and mitochondrial hyperfusion. Metabolomics confirmed an upregulation of the pentose phosphate pathway and the TCA cycle. Fumarate was also increased, suggesting an increase in flux through complex II. Changes in lipid metabolism included an upregulation in cardiolipin and de novo triacylglyceride biosynthesis, along with increasing numbers of lipid droplets. Conclusion: Prolonged exposure to IL-1b induces metabolic rewiring in CECs that results in an increase in spare respiratory capacity. These findings suggest that the corneal epithelium is able to adapt to certain levels of chronic inflammation and may have important implications in our understanding of immune tone and cellular stress responses in ocular surface epithelia.
{"title":"IL-1b-mediated Immunometabolic Adaptation in Corneal Epithelial Cells","authors":"Jose Marcos Sanches, Rajalakshmy Ayilam Ramachandran, Natalia Mussi, Hamid Baniasadi, Danielle M Robertson","doi":"10.1101/2024.09.08.611874","DOIUrl":"https://doi.org/10.1101/2024.09.08.611874","url":null,"abstract":"Purpose: As an external mucosal surface, the corneal epithelium is subject to a barrage of stressors that are known to trigger inflammation. IL-1b, a master regulator of inflammation, is secreted into the preocular tear film by ocular surface epithelial cells and infiltrating immune cells. While increased levels of IL-1b have been associated with corneal disease, the effects of IL-1b on mitochondrial function in corneal epithelial cells (CECs) is unknown.\u0000Methods: To investigate the effects of IL-1b on mitochondrial function, telomerase immortalized human CECs were cultured in either 50 ng/mL or 100 ng/mL IL-1b for short term (24 hours) or prolonged (72 hours) time periods. Cells were assessed for ROS, inflammatory cytokine production, mitochondrial polarization and ultrastructure, mitophagy, and changes in the metabolite composition. Lipid drops were examined using light and fluorescent microscopy.\u0000Results: Short term exposure to IL-1b triggered an increase in IL-8 and ROS levels that corresponded to a reduction in mitochondrial membrane potential. Long term exposure also showed increased levels of IL-8 and IL-6 and further increased ROS. After long term exposure however, there was a paradoxical increase in mitochondrial membrane potential that was associated an increase in spare respiratory capacity and mitochondrial hyperfusion. Metabolomics confirmed an upregulation of the pentose phosphate pathway and the TCA cycle. Fumarate was also increased, suggesting an increase in flux through complex II. Changes in lipid metabolism included an upregulation in cardiolipin and de novo triacylglyceride biosynthesis, along with increasing numbers of lipid droplets. Conclusion: Prolonged exposure to IL-1b induces metabolic rewiring in CECs that results in an increase in spare respiratory capacity. These findings suggest that the corneal epithelium is able to adapt to certain levels of chronic inflammation and may have important implications in our understanding of immune tone and cellular stress responses in ocular surface epithelia.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.07.611784
Melanie Rose Walker, Preston Leung, Elizabeth Keoshkerian, Mehdi R Pirozyan, Andrew Lloyd, Fabio Luciani, Rowena A Bull
Numerous studies have shown that viral variants that elude the host immune response may incur a fitness expense, diminishing the survival of the viral strain within the host, and the capacity of the variant to survive future transmission events. Furthermore, co-occurring mutations outside the epitope regions targeted by the immune response may increase or decrease the likelihood of survival of the variant (known as epistasis). Analysis of viral fitness and epistasis over the non-structural protein regions is lacking for hepatitis C virus (HCV). Here, using a rare cohort of subjects very recently infected with HCV, we build upon our prior investigations by integrating mathematical modelling and experimental data to examine the interplay between the evolving transmitted/founder (T/F) viruses, the adaptive immune response, viral fitness, and co-occurring mutations. We show that viral fitness decreases during the first 90 days post-infection (DPI) associated with the magnitude of CD8+ T-cell responses and the initial level of diversification. Thereafter, viral fitness rebounds in a complex pattern of evolution characterized by multiple sets of co-occurring mutations. Finally, we show that an early and strong CD8+ T-cell response in the absence of neutralizing antibodies (nAbs) imposes a strong selective force on the T/F virus population, enabling the virus to escape and establish chronic infection. Understanding these dynamics is highly relevant for HCV vaccine design and supports a vaccine strategy that induces broad immunity targeting both T and B cell responses.
大量研究表明，躲过宿主免疫反应的病毒变异体可能会产生适应性代价，降低病毒株在宿主体内的存活率以及变异体在未来传播事件中的存活能力。此外，在免疫反应所针对的表位区之外同时出现的变异可能会增加或减少变异体存活的可能性（称为表位）。丙型肝炎病毒（HCV）缺乏对病毒适应性和非结构蛋白区表位的分析。在此，我们利用一组最近感染 HCV 的罕见受试者，通过整合数学模型和实验数据来研究不断进化的传播/创始（T/F）病毒、适应性免疫反应、病毒适应性和共存突变之间的相互作用，从而在先前研究的基础上更进一步。我们的研究表明，在感染后的前 90 天（DPI），病毒的适应性会下降，这与 CD8+ T 细胞反应的程度和最初的多样化水平有关。此后，病毒适应性在以多组并发突变为特征的复杂进化模式中反弹。最后，我们表明，在没有中和抗体（nAbs）的情况下，早期强烈的 CD8+ T 细胞反应会对 T/F 病毒群体产生强大的选择性力量，使病毒得以逃脱并建立慢性感染。了解这些动态变化与 HCV 疫苗的设计高度相关，并有助于制定一种同时针对 T 细胞和 B 细胞反应诱导广泛免疫力的疫苗策略。
{"title":"Temporal dynamics of viral fitness and the adaptive immune response in HCV infection","authors":"Melanie Rose Walker, Preston Leung, Elizabeth Keoshkerian, Mehdi R Pirozyan, Andrew Lloyd, Fabio Luciani, Rowena A Bull","doi":"10.1101/2024.09.07.611784","DOIUrl":"https://doi.org/10.1101/2024.09.07.611784","url":null,"abstract":"Numerous studies have shown that viral variants that elude the host immune response may incur a fitness expense, diminishing the survival of the viral strain within the host, and the capacity of the variant to survive future transmission events. Furthermore, co-occurring mutations outside the epitope regions targeted by the immune response may increase or decrease the likelihood of survival of the variant (known as epistasis). Analysis of viral fitness and epistasis over the non-structural protein regions is lacking for hepatitis C virus (HCV). Here, using a rare cohort of subjects very recently infected with HCV, we build upon our prior investigations by integrating mathematical modelling and experimental data to examine the interplay between the evolving transmitted/founder (T/F) viruses, the adaptive immune response, viral fitness, and co-occurring mutations. We show that viral fitness decreases during the first 90 days post-infection (DPI) associated with the magnitude of CD8+ T-cell responses and the initial level of diversification. Thereafter, viral fitness rebounds in a complex pattern of evolution characterized by multiple sets of co-occurring mutations. Finally, we show that an early and strong CD8+ T-cell response in the absence of neutralizing antibodies (nAbs) imposes a strong selective force on the T/F virus population, enabling the virus to escape and establish chronic infection. Understanding these dynamics is highly relevant for HCV vaccine design and supports a vaccine strategy that induces broad immunity targeting both T and B cell responses.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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