bioRxiv - Immunology最新文献_第5页

Adjuvant-dependent impacts on vaccine-induced humoral responses and protection in preclinical models of nasal and genital colonization by pathogenic Neisseria 佐剂对疫苗诱导的体液反应和致病性奈瑟氏菌鼻腔和生殖器定植临床前模型的保护作用的影响

bioRxiv - Immunology Pub Date : 2024-09-12 DOI: 10.1101/2024.09.07.611809

Epshita A. Islam, Jamie E. Fegan, Joseph J. Zeppa, Sang K. Ahn, Dixon Ng, Elissa G. Currie, Jessica Lam, Trevor F. Moraes, Scott D. Gray-Owen

{"title":"Adjuvant-dependent impacts on vaccine-induced humoral responses and protection in preclinical models of nasal and genital colonization by pathogenic Neisseria","authors":"Epshita A. Islam, Jamie E. Fegan, Joseph J. Zeppa, Sang K. Ahn, Dixon Ng, Elissa G. Currie, Jessica Lam, Trevor F. Moraes, Scott D. Gray-Owen","doi":"10.1101/2024.09.07.611809","DOIUrl":"https://doi.org/10.1101/2024.09.07.611809","url":null,"abstract":"Neisseria gonorrhoeae, which causes the sexually transmitted infection gonorrhea and N. meningitidis, a leading cause of bacterial meningitis and septicemia, are closely related human-restricted pathogens that inhabit distinct primary mucosal niches. While successful vaccines against invasive meningococcal disease have been available for decades, the rapid rise in antibiotic resistance has led to an urgent need to develop an effective gonococcal vaccine. Several surface antigens are shared among these two pathogens, making cross-species protection an exciting prospect. However, the type of vaccine-mediated immune response required to achieve protection against respiratory versus genital infection remains ill defined. In this study, we utilize well established mouse models of female lower genital tract colonization by N. gonorrhoeae and upper respiratory tract colonization by N. meningitidis to examine the performance of transferrin binding protein B (TbpB) vaccines formulated with immunologically distinct vaccine adjuvants. We demonstrate that vaccine-mediated protection is influenced by the choice of adjuvant, with Th1/2-balanced adjuvants performing optimally against N. gonorrhoeae, and both Th1/2-balanced and Th2-skewing adjuvants leading to a significant reduction in N. meningitidis burden. We further establish a lack of correlation between protection status and the humoral response or bactericidal titre. Combined, this work provides supports the feasibility for a single vaccine formulation to achieve pan-neisserial coverage.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211216","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}

引用次数: 0

Adjuvant conditioning shapes the adaptive immune response and promotes trained immunotolerance via NLRP3/IL-1 辅助调节通过 NLRP3/IL-1 塑造适应性免疫反应并促进训练有素的免疫耐受性

bioRxiv - Immunology Pub Date : 2024-09-12 DOI: 10.1101/2024.09.06.611736

Thais Boccia, Weikang Pan, Victor Fattori, Rodrigo Cervantes-Diaz, Michael S. Rogers, Ivan Zanoni, Alex G. Cuenca

{"title":"Adjuvant conditioning shapes the adaptive immune response and promotes trained immunotolerance via NLRP3/IL-1","authors":"Thais Boccia, Weikang Pan, Victor Fattori, Rodrigo Cervantes-Diaz, Michael S. Rogers, Ivan Zanoni, Alex G. Cuenca","doi":"10.1101/2024.09.06.611736","DOIUrl":"https://doi.org/10.1101/2024.09.06.611736","url":null,"abstract":"Trained immunity enhances responsiveness of the innate immune system upon restimulation. Although adjuvants are used to enhance immune responses, we showed that repeated administration of alum, termed adjuvant conditioning (AC), establishes an immunosuppressive environment that delays allogeneic graft rejection by expanding myeloid-derived suppressor cells (MDSCs). Here, we show that AC-induced MDSCs suppress antigen specific adaptive responses both in vitro and in vivo, and that the immunosuppression is abolished in the absence of NLRP3 and IL-1 signaling. Allogeneic pancreatic islets transplanted into AC-treated NLRP3-/- mice are not protected, demonstrating that AC requires NLRP3 signaling. Finally, AC also has an immunosuppressive effect on human PBMCs. Overall, our data show that AC establishes an immunosuppressive milieu via the NLRP3/IL-1 axis, leading to trained immunosuppression, or trained tolerance. Our findings give a potent mandate to explore the possibility to target the NLRP3/IL-1 pathway as a new promising strategy to condition transplant recipients and promote allograft tolerance.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"80 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211217","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}

引用次数: 0

Simulating CD8 T Cell Exhaustion: A Comprehensive Approach 模拟 CD8 T 细胞耗竭：综合方法

bioRxiv - Immunology Pub Date : 2024-09-11 DOI: 10.1101/2024.09.06.611697

Andrea J Manrique-Rincon, Ben Foster, Stuart Horswell, David A Goulding, David J Adams, Anneliese O Speak

{"title":"Simulating CD8 T Cell Exhaustion: A Comprehensive Approach","authors":"Andrea J Manrique-Rincon, Ben Foster, Stuart Horswell, David A Goulding, David J Adams, Anneliese O Speak","doi":"10.1101/2024.09.06.611697","DOIUrl":"https://doi.org/10.1101/2024.09.06.611697","url":null,"abstract":"Immunotherapy has revolutionised the treatment of multiple cancer types, however, these treatments only work for a proportion of patients and biomarkers to predict response are lacking. One correlate of response is the reinvigoration of a subset of CD8 T cells that have an exhausted phenotype and impaired functionality. In order to develop new therapies, reproducible models are required to identify candidate target genes that enables the reversal of key hallmarks of T cell exhaustion. Here we describe the development of an in vitro model by chronically stimulating T cells with their cognate antigen and performed an in depth temporal phenotypic characterisation. This model recapitulates many of the critical hallmarks of exhaustion, including increased expression of canonical exhaustion surface markers, impaired proliferation, reduced cytokine production, decreased release of cytotoxic granules, and metabolic alterations, including dysfunctional mitochondria. These exhaustion hallmarks were validated using an in vivo model and a gene signature identified which robustly define the shared in vitro and in vivo exhausted state. Critically, this signature is also observed in tumour infiltrating T cells from multiple human tumour types, validating the translational potential of this model for discovering and triaging new therapies.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226773","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}

引用次数: 0

CRISPR editing of candidate host factors that impact influenza A virus infection 对影响甲型流感病毒感染的候选宿主因子进行 CRISPR 编辑

bioRxiv - Immunology Pub Date : 2024-09-11 DOI: 10.1101/2024.09.10.612185

Pyae P. Kyawe, Ping Liu, Zhaozhao Jiang, Evan S. Bradley, Thomas Cicuto, Melanie I Trombly, Neal Silverman, Katherine Fitzgerald, William M. McDougall, Jennifer P. Wang

{"title":"CRISPR editing of candidate host factors that impact influenza A virus infection","authors":"Pyae P. Kyawe, Ping Liu, Zhaozhao Jiang, Evan S. Bradley, Thomas Cicuto, Melanie I Trombly, Neal Silverman, Katherine Fitzgerald, William M. McDougall, Jennifer P. Wang","doi":"10.1101/2024.09.10.612185","DOIUrl":"https://doi.org/10.1101/2024.09.10.612185","url":null,"abstract":"Influenza A virus (IAV) is a respiratory pathogen with a segmented negative-sense RNA genome that can cause epidemics and pandemics. The host factors required for the complete IAV infectious cycle have not been fully identified. Here, we examined select host factors that were identified by independent CRISPR screens as candidate contributors to IAV infectivity. We performed CRISPR-mediated knockout of cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS) as well as CRISPR-mediated overexpression of beta-1,4 N-acetylgalactosaminyltransferase 2 (B4GALNT2) and adenosine deaminase acting on RNA 1 (ADAR1) in the human bronchial epithelial A549 cell line and evaluated IAV infectivity. We confirmed that the knockout of CMAS or overexpression of B4GALNT2 restricts IAV infection by diminishing binding to the cell surface but has no effect on vesicular stomatitis virus infection. While ADAR1 overexpression does not significantly inhibit IAV replication, it has a pro-viral effect with coxsackie B virus (CVB) infection. This pro-viral effect is not likely secondary to reduced type I interferon (IFN) production, as the induction of the IFN-stimulated genes ISG15 and CXCL10 is negligible in both parent and ADAR1-overexpressing A549 cells following CVB challenge. In contrast, ISG15 and CXCL10 production is robust and equal for parent and ADAR1-overexpressing A549 cells challenged with IAV. Taken together, these data provide insight into how host factors identified in CRISPR screens can be further explored to understand the dynamics of pro- and anti-viral factors.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211219","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}

引用次数: 0

The Cardioprotective Role of Neutrophil-Specific STING in Myocardial Ischemia/Reperfusion Injury 中性粒细胞特异性 STING 在心肌缺血/再灌注损伤中的心脏保护作用

bioRxiv - Immunology Pub Date : 2024-09-11 DOI: 10.1101/2024.09.06.611551

Maegan L Brockman, Triniti A Scruggs, Lanfang Wang, Gabriella Kabboul, John W Calvert, Rebecca D Levit

{"title":"The Cardioprotective Role of Neutrophil-Specific STING in Myocardial Ischemia/Reperfusion Injury","authors":"Maegan L Brockman, Triniti A Scruggs, Lanfang Wang, Gabriella Kabboul, John W Calvert, Rebecca D Levit","doi":"10.1101/2024.09.06.611551","DOIUrl":"https://doi.org/10.1101/2024.09.06.611551","url":null,"abstract":"Background: Neutrophils are the most rapid and abundant immune cells to infiltrate the myocardium following myocardial ischemia/reperfusion injury (MI/R). Neutrophil heterogeneity has not been well characterized in MI/R, and studies have shown conflicting results regarding the impact of neutrophil depletion on cardiac injury. We thus aim to study the impact of neutrophils with enriched type I interferon signature and the role of STING (stimulator of interferon genes) signaling in neutrophils on cardiac reperfusion injury. Methods: We utilized single-cell RNA sequencing to study neutrophil heterogeneity in response to MI/R. We generated a neutrophil-specific STING knockout mouse to assess the role of neutrophil STING in a model of MI/R. We examined cardiac function following injury via echocardiography and assessed the immune cell trajectory following injury utilizing flow cytometry. Results: We identified a population of neutrophils with enriched type I interferon signaling and response to type I interferon following MI/R. We found that genetic deletion of neutrophil-specific STING led to worsened cardiac function following MI/R. Further investigation of the immune response by flow cytometry revealed decreased neutrophil infiltration into the myocardium and a shift in macrophage polarization. Conclusions: Our findings suggest that neutrophil-specific STING is cardioprotective in MI/R, partly due to its effects on downstream immune cells. These results demonstrate that early alterations or therapeutic interventions can influence key events in the resolution of inflammation following MI/R.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211218","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}

引用次数: 0

Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight 肥胖和体重健康患者早期 NK 细胞和 T 细胞功能失调标志着病情恶化为重症登革热

bioRxiv - Immunology Pub Date : 2024-09-11 DOI: 10.1101/2024.09.06.611687

Michaela Gregorova, Marianna Santopaolo, Lucy C Garner, Divya Diamond, Narayan Ramamurthy, Vi Tran, Nguyet Nguyen Minh, Eben Jones, Mike Nsubuga, Curtis Luscombe, Hoa Vo Thi My, Ho Quang Chanh, Nguyen Thi Xuan Chau, Dong Thi Hoai Tam, Duyen Huynh Thi Le, Cao Thi Tam, Paul Klenerman, Sophie Yacoub, Laura Rivino

{"title":"Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight","authors":"Michaela Gregorova, Marianna Santopaolo, Lucy C Garner, Divya Diamond, Narayan Ramamurthy, Vi Tran, Nguyet Nguyen Minh, Eben Jones, Mike Nsubuga, Curtis Luscombe, Hoa Vo Thi My, Ho Quang Chanh, Nguyen Thi Xuan Chau, Dong Thi Hoai Tam, Duyen Huynh Thi Le, Cao Thi Tam, Paul Klenerman, Sophie Yacoub, Laura Rivino","doi":"10.1101/2024.09.06.611687","DOIUrl":"https://doi.org/10.1101/2024.09.06.611687","url":null,"abstract":"Dengue is a mosquito-borne virus infection affecting half of the world's population for which therapies are lacking. The role of T and NK-cells in protection/immunopathogenesis remains unclear for dengue. We performed a longitudinal phenotypic, functional and transcriptional analyses of T and NK-cells in 124 dengue patients using flow cytometry and single-cell RNA-sequencing. We show that T/NK-cell signatures early in infection discriminate patients who will progress to severe dengue (SD) from those who do not. In patients with overweight/obesity these signatures are exacerbated compared to healthy weight patients, supporting their increased susceptibility to SD. In SD, CD4+/CD8+ T-cells and NK-cells display increased co-inhibitory receptor expression and decreased cytotoxic capacity compared to non-SD. Furthermore, type-I Interferon signalling is downregulated in SD, suggesting defective virus-sensing mechanisms may underlie NK/T-cell dysfunction. We propose that dysfunctional \"professional killer\" T/NK-cells underpin dengue pathogenesis. Our findings pave the way for the evaluation of immunomodulatory therapies for dengue.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211221","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}

引用次数: 0

Single-stranded HDR templates with truncated Cas12a binding sequences improve knock-in efficiencies in primary human T cells 带有截短 Cas12a 结合序列的单链 HDR 模板可提高原代人类 T 细胞的基因敲入效率

bioRxiv - Immunology Pub Date : 2024-09-11 DOI: 10.1101/2024.09.11.608426

Ana-Maria Nitulescu, Weijie Du, Viktor Glaser, Jonas Kath, Robert Greensmith, Nanna S Mikkelsen, Maik Stein, Rasmus Bak, Michael Kaminski, Dimitrios Laurin Wagner

{"title":"Single-stranded HDR templates with truncated Cas12a binding sequences improve knock-in efficiencies in primary human T cells","authors":"Ana-Maria Nitulescu, Weijie Du, Viktor Glaser, Jonas Kath, Robert Greensmith, Nanna S Mikkelsen, Maik Stein, Rasmus Bak, Michael Kaminski, Dimitrios Laurin Wagner","doi":"10.1101/2024.09.11.608426","DOIUrl":"https://doi.org/10.1101/2024.09.11.608426","url":null,"abstract":"Non-viral gene editing via CRISPR-Cas12a offers an alternative to Cas9-based methods, providing better targeting of AT-rich regions, simplified guide RNA manufacturing, and high specificity. However, the efficacy of editing outcomes is subject to various factors, with tem-plate format playing a crucial role. Currently, the predominant non-viral template format for inducing homology-directed repair (HDR) after nuclease-induced DNA breaks is double-stranded DNA (dsDNA), which is toxic when transfected at high doses. Previous studies have demonstrated that using single-stranded DNA (ssDNA) with flanking double-stranded Cas-target-sequences (CTS) as a repair template for Cas9-mediated gene editing can miti-gate this toxicity and increase knock-in efficiency. Here, we investigate CTS design for As-Cas12a Ultra by exploring PAM orientation and binding requirements of the Cas12a-crRNA complex. Additionally, we rule out in-vitro ssDNase activity of AsCas12a Ultra under cell-physiological Mg2+ conditions. Finally, we showcase the advantage of using ssDNA with double-stranded CTS end modifications (ssCTS) at high doses for delivering clinically relevant transgenes of varying sizes into three T-cell receptor-CD3 complex genes (TRAC, CD3ζ, CD3ϵ), achieving up to 90% knock-in rates for a 0.8kb insert at the CD3ϵ locus. Overall, AsCas12a Ultra and ssCTS donors represent a platform for highly efficient knock-in in primary human T cells with minimal toxicity.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211220","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}

引用次数: 0

Immune Cell Influence on Diffuse Large B-Cell Lymphoma: A Mendelian Randomization Analysis 免疫细胞对弥漫大 B 细胞淋巴瘤的影响：孟德尔随机分析

bioRxiv - Immunology Pub Date : 2024-09-10 DOI: 10.1101/2024.09.05.611435

Honghua He, Jihong Zhong, Qinghua Li, Chen Deng, Xin Yuan, Kaixiang Zhang, Lirong Nie, Nali Cai

{"title":"Immune Cell Influence on Diffuse Large B-Cell Lymphoma: A Mendelian Randomization Analysis","authors":"Honghua He, Jihong Zhong, Qinghua Li, Chen Deng, Xin Yuan, Kaixiang Zhang, Lirong Nie, Nali Cai","doi":"10.1101/2024.09.05.611435","DOIUrl":"https://doi.org/10.1101/2024.09.05.611435","url":null,"abstract":"Objective: To elucidate the causal relationship between immune cells and diffuse large B-cell lymphoma (DLBCL), we conducted a Mendelian randomization analysis.\u0000Methods: Mendelian randomization (MR) leverages genetic variants as instruments to infer causal effects from observational data. Here, we performed a two-sample MR analysis to assess the causal impact of 731 immune cell types on DLBCL. We employed various MR techniques, including the weighted median estimator (WME) and inverse variance weighting (IVW), and conducted sensitivity analyses to ensure result robustness. Additionally, reverse MR analysis was performed to explore the potential causal relationship between DLBCL and immune cells.\u0000Results: We identified seventeen immune features with causal links to DLBCL, categorized across various cellular groups: four in B cells, two in T cell maturation stages, six in Tregs, four in the TBNK group, and one in dendritic cells (DCs). Sensitivity analyses confirmed the absence of heterogeneity, horizontal pleiotropy, and bias in our findings. Reverse causal analysis revealed a causal association between DLBCL and one of the seventeen immune cell types identified.\u0000Conclusions: Our MR analysis of seventeen immune cell types uncovers the complex interactions between the immune system and DLBCL, providing crucial insights into the tumor microenvironment and potential avenues for targeted immunotherapy.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"410 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211264","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}

引用次数: 0

Autoantigen TRIM21 (Ro52) assembles pro-inflammatory immune complexes following lytic cell death 自体抗原 TRIM21 (Ro52) 在细胞溶解性死亡后形成促炎免疫复合物

bioRxiv - Immunology Pub Date : 2024-09-10 DOI: 10.1101/2024.09.06.611470

Esther L Jones, Benjamin Demarco, Madelon ML de Jong, Han Cai, Sarah Hill, Ryan E. Glass, Gemma Harris, Saba Nayar, Benjamin A Fisher, Audrey Gerard, Jelena S Bezbradica, Lynn B Dustin

{"title":"Autoantigen TRIM21 (Ro52) assembles pro-inflammatory immune complexes following lytic cell death","authors":"Esther L Jones, Benjamin Demarco, Madelon ML de Jong, Han Cai, Sarah Hill, Ryan E. Glass, Gemma Harris, Saba Nayar, Benjamin A Fisher, Audrey Gerard, Jelena S Bezbradica, Lynn B Dustin","doi":"10.1101/2024.09.06.611470","DOIUrl":"https://doi.org/10.1101/2024.09.06.611470","url":null,"abstract":"Sjögren's disease (SjD) causes localised and systemic inflammation due to autoantibody production against intracellular proteins, such as TRIM21/Ro52. TRIM21 is an E3 ubiquitin ligase which binds antibody Fc domains on opsonised pathogens, which have escaped extracellular immunity and entered cytosols; TRIM21 ubiquitinates these, driving their proteasomal degradation. How and why TRIM21 becomes an autoantigen remains unclear. We show that TRIM21 is released upon lytic cell death (pyroptosis/necroptosis) but not apoptosis. Released TRIM21 binds circulating antibody Fc domains, and forms large immune complexes (ICs). These are further enhanced with TRIM21/Ro52 seropositive SjD plasma antibodies, where interactions are mediated via both Fc and F(ab')2 domains. TRIM21-ICs are taken up by macrophages, which in high interferon environments drive pro-inflammatory responses, antigen presentation, and inflammatory and metabolic transcriptional changes. Whilst many cytosolic proteins are released by dead cells, due to its high affinity for antibodies, TRIM21 can generate large ICs. This may perpetuate inflammation and antigen presentation, causing TRIM21 to be highly autoimmunogenic.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142211224","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}

引用次数: 0

CD200 depletion in glioma enhances antitumor immunity and induces tumor rejection 清除胶质瘤中的 CD200 可增强抗肿瘤免疫力并诱导肿瘤排斥反应

bioRxiv - Immunology Pub Date : 2024-09-10 DOI: 10.1101/2024.09.08.611922

Itay Raphael, Anzar A Mujeeb, Elisabet Ampudia-Mesias, ReidAnn E Sever, Brandon McClellan, Stephen C Frederico, Chaim T Sneiderman, Apoorva Mirji, Ali Daba, Francisco Puerta-Martinez, Michal Nisnboym, Wilson B Edwards, Michael Graner, Christopher Moertel, Maria G Castro, Gary Kohanbash, Michael Olin

{"title":"CD200 depletion in glioma enhances antitumor immunity and induces tumor rejection","authors":"Itay Raphael, Anzar A Mujeeb, Elisabet Ampudia-Mesias, ReidAnn E Sever, Brandon McClellan, Stephen C Frederico, Chaim T Sneiderman, Apoorva Mirji, Ali Daba, Francisco Puerta-Martinez, Michal Nisnboym, Wilson B Edwards, Michael Graner, Christopher Moertel, Maria G Castro, Gary Kohanbash, Michael Olin","doi":"10.1101/2024.09.08.611922","DOIUrl":"https://doi.org/10.1101/2024.09.08.611922","url":null,"abstract":"High-grade gliomas are a major health challenge with poor prognosis and high morbidity. Immune-checkpoint inhibitors (ICI) have emerged as promising therapeutic options for several malignancies yet show little efficacy against central nervous system (CNS) tumors. CD200 is a newly recognized immune checkpoint that modulates immune homeostasis. CD200 protein is expressed by a variety of cells, including immune cells and stromal cells, and is overexpressed by many tumors. The shedding of CD200 from tumor cells can create an immunosuppressive environment that dampens anti-tumor immunity by modulating cytolytic activity and cytokine expression both within and outside the tumor microenvironment (TME). While it is well-accepted that CD200 induces a pro-tumorigenic environment through its ability to suppress the immune response, we sought to determine the role of glioma-specific expression of CD200. We show that CD200 is expressed across glioma types, is shed from tumor cells, and increases over time in the serum of patients undergoing immunotherapy. Using CD200 knockout (KO) glioma models, we demonstrated that glioma cell-derived CD200 promotes tumor growth in vivo and in vitro. Notably, CD200 KO gliomas are spontaneously rejected by their host, a process that required a fully functional immune system, including NK and T-cells. Moreover, we report that glioma-derived or brain-injected soluble CD200 contributes to the suppression of antigen-specific CD8 T-cells in the draining lymph nodes (dLNs). Our work provides new mechanistic insights regarding CD200-mediated immunosuppression by gliomas.","PeriodicalId":501182,"journal":{"name":"bioRxiv - Immunology","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226774","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}

引用次数: 0