Pub Date : 2023-07-19eCollection Date: 2023-01-01DOI: 10.1093/discim/kyad008
Ye Chean Teh, Ming Yao Chooi, Shu Zhen Chong
Monocytes are circulating myeloid cells that are derived from dedicated progenitors in the bone marrow. Originally thought of as mere precursors for the replacement of tissue macrophages, it is increasingly clear that monocytes execute distinct effector functions and may give rise to monocyte-derived cells with unique properties from tissue-resident macrophages. Recently, the advent of novel experimental approaches such as single-cell analysis and fate-mapping tools has uncovered an astonishing display of monocyte plasticity and heterogeneity, which we believe has emerged as a key theme in the field of monocyte biology in the last decade. Monocyte heterogeneity is now recognized to develop as early as the progenitor stage through specific imprinting mechanisms, giving rise to specialized effector cells in the tissue. At the same time, monocytes must overcome their susceptibility towards cellular death to persist as monocyte-derived cells in the tissues. Environmental signals that preserve their heterogenic phenotypes and govern their eventual fates remain incompletely understood. In this review, we will summarize recent advances on the developmental trajectory of monocytes and discuss emerging concepts that contributes to the burgeoning field of monocyte plasticity and heterogeneity.
{"title":"Behind the monocyte's mystique: uncovering their developmental trajectories and fates.","authors":"Ye Chean Teh, Ming Yao Chooi, Shu Zhen Chong","doi":"10.1093/discim/kyad008","DOIUrl":"10.1093/discim/kyad008","url":null,"abstract":"<p><p>Monocytes are circulating myeloid cells that are derived from dedicated progenitors in the bone marrow. Originally thought of as mere precursors for the replacement of tissue macrophages, it is increasingly clear that monocytes execute distinct effector functions and may give rise to monocyte-derived cells with unique properties from tissue-resident macrophages. Recently, the advent of novel experimental approaches such as single-cell analysis and fate-mapping tools has uncovered an astonishing display of monocyte plasticity and heterogeneity, which we believe has emerged as a key theme in the field of monocyte biology in the last decade. Monocyte heterogeneity is now recognized to develop as early as the progenitor stage through specific imprinting mechanisms, giving rise to specialized effector cells in the tissue. At the same time, monocytes must overcome their susceptibility towards cellular death to persist as monocyte-derived cells in the tissues. Environmental signals that preserve their heterogenic phenotypes and govern their eventual fates remain incompletely understood. In this review, we will summarize recent advances on the developmental trajectory of monocytes and discuss emerging concepts that contributes to the burgeoning field of monocyte plasticity and heterogeneity.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47813442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-19eCollection Date: 2023-01-01DOI: 10.1093/discim/kyad009
Stefano A P Colombo, Sheila L Brown, Matthew R Hepworth, Jenny Hankinson, Felice Granato, Semra J Kitchen, Tracy Hussell, Angela Simpson, Peter C Cook, Andrew S MacDonald
The lung is a dynamic mucosal surface constantly exposed to a variety of immunological challenges including harmless environmental antigens, pollutants, and potentially invasive microorganisms. Dysregulation of the immune system at this crucial site is associated with a range of chronic inflammatory conditions including asthma and Chronic Pulmonary Obstructive Disease (COPD). However, due to its relative inaccessibility, our fundamental understanding of the human lung immune compartment is limited. To address this, we performed flow cytometric immune phenotyping of human lung tissue and matched blood samples that were isolated from 115 donors undergoing lung tissue resection. We provide detailed characterization of the lung mononuclear phagocyte and T cell compartments, demonstrating clear phenotypic differences between lung tissue cells and those in peripheral circulation. Additionally, we show that CD103 expression demarcates pulmonary T cells that have undergone recent TCR and IL-7R signalling. Unexpectedly, we discovered that the immune landscape from asthmatic or COPD donors was broadly comparable to controls. Our data provide a much-needed expansion of our understanding of the pulmonary immune compartment in both health and disease.
肺部是一个动态的粘膜表面,经常暴露在各种免疫挑战之下,包括无害的环境抗原、污染物和潜在的入侵微生物。免疫系统在这一关键部位的失调与一系列慢性炎症有关,包括哮喘和慢性肺阻塞性疾病(COPD)。然而,由于其相对不可接近性,我们对人体肺部免疫区的基本了解十分有限。为了解决这个问题,我们对从 115 名接受肺组织切除术的供体中分离出来的人肺组织和匹配的血液样本进行了流式细胞免疫表型分析。我们详细描述了肺单核吞噬细胞和 T 细胞区系的特征,显示了肺组织细胞和外周循环细胞之间明显的表型差异。此外,我们还发现,CD103 的表达可将肺部 T 细胞区分为近期接受过 TCR 和 IL-7R 信号传导的细胞。意想不到的是,我们发现哮喘或慢性阻塞性肺病供体的免疫状况与对照组大致相当。我们的数据为我们了解健康和疾病中的肺部免疫区提供了亟需的拓展。
{"title":"Comparative phenotype of circulating versus tissue immune cells in human lung and blood compartments during health and disease.","authors":"Stefano A P Colombo, Sheila L Brown, Matthew R Hepworth, Jenny Hankinson, Felice Granato, Semra J Kitchen, Tracy Hussell, Angela Simpson, Peter C Cook, Andrew S MacDonald","doi":"10.1093/discim/kyad009","DOIUrl":"10.1093/discim/kyad009","url":null,"abstract":"<p><p>The lung is a dynamic mucosal surface constantly exposed to a variety of immunological challenges including harmless environmental antigens, pollutants, and potentially invasive microorganisms. Dysregulation of the immune system at this crucial site is associated with a range of chronic inflammatory conditions including asthma and Chronic Pulmonary Obstructive Disease (COPD). However, due to its relative inaccessibility, our fundamental understanding of the human lung immune compartment is limited. To address this, we performed flow cytometric immune phenotyping of human lung tissue and matched blood samples that were isolated from 115 donors undergoing lung tissue resection. We provide detailed characterization of the lung mononuclear phagocyte and T cell compartments, demonstrating clear phenotypic differences between lung tissue cells and those in peripheral circulation. Additionally, we show that CD103 expression demarcates pulmonary T cells that have undergone recent TCR and IL-7R signalling. Unexpectedly, we discovered that the immune landscape from asthmatic or COPD donors was broadly comparable to controls. Our data provide a much-needed expansion of our understanding of the pulmonary immune compartment in both health and disease.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10403752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9952332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-24eCollection Date: 2023-01-01DOI: 10.1093/discim/kyad007
Arlisa Alisjahbana, Imran Mohammad, Yu Gao, Elza Evren, Tim Willinger
Innate lymphoid cells (ILCs) are sentinels of healthy organ function, yet it is unknown how ILCs adapt to distinct anatomical niches within tissues. Here, we used a unique humanized mouse model, MISTRG mice transplanted with human hematopoietic stem and progenitor cells (HSPCs), to define the gene signatures of human ILCs in the vascular versus the tissue (extravascular) compartment of the lung. Single-cell RNA sequencing in combination with intravascular cell labeling demonstrated that heterogeneous populations of human ILCs and natural killer (NK) cells occupied the vascular and tissue niches in the lung of HSPC-engrafted MISTRG mice. Moreover, we discovered that niche-specific cues shape the molecular programs of human ILCs in the distinct sub-anatomical compartments of the lung. Specifically, extravasation of ILCs into the lung tissue was associated with the upregulation of genes involved in the acquisition of tissue residency, cell positioning within the lung, sensing of tissue-derived signals, cellular stress responses, nutrient uptake, and interaction with other tissue-resident immune cells. We also defined a core tissue signature shared between human ILCs and NK cells in the extravascular space of the lung, consistent with imprinting by signals from the local microenvironment. The molecular characterization of human ILCs and NK cells in the vascular and tissue niches of the lung provides new knowledge on the mechanisms of ILC tissue adaptation and represents a resource for further studies.
{"title":"Single-cell RNA sequencing of human lung innate lymphoid cells in the vascular and tissue niche reveals molecular features of tissue adaptation.","authors":"Arlisa Alisjahbana, Imran Mohammad, Yu Gao, Elza Evren, Tim Willinger","doi":"10.1093/discim/kyad007","DOIUrl":"10.1093/discim/kyad007","url":null,"abstract":"<p><p>Innate lymphoid cells (ILCs) are sentinels of healthy organ function, yet it is unknown how ILCs adapt to distinct anatomical niches within tissues. Here, we used a unique humanized mouse model, MISTRG mice transplanted with human hematopoietic stem and progenitor cells (HSPCs), to define the gene signatures of human ILCs in the vascular versus the tissue (extravascular) compartment of the lung. Single-cell RNA sequencing in combination with intravascular cell labeling demonstrated that heterogeneous populations of human ILCs and natural killer (NK) cells occupied the vascular and tissue niches in the lung of HSPC-engrafted MISTRG mice. Moreover, we discovered that niche-specific cues shape the molecular programs of human ILCs in the distinct sub-anatomical compartments of the lung. Specifically, extravasation of ILCs into the lung tissue was associated with the upregulation of genes involved in the acquisition of tissue residency, cell positioning within the lung, sensing of tissue-derived signals, cellular stress responses, nutrient uptake, and interaction with other tissue-resident immune cells. We also defined a core tissue signature shared between human ILCs and NK cells in the extravascular space of the lung, consistent with imprinting by signals from the local microenvironment. The molecular characterization of human ILCs and NK cells in the vascular and tissue niches of the lung provides new knowledge on the mechanisms of ILC tissue adaptation and represents a resource for further studies.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11034571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41850609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-04-18eCollection Date: 2023-01-01DOI: 10.1093/discim/kyad005
Andrew Muir, Alex Bennett, Hannah Smith, Larisa Logunova, Andrew Wolfenden, Jonathan Fenn, Ann E Lowe, Andy Brass, John R Grainger, Joanne E Konkel, Janette E Bradley, Iris Mair, Kathryn J Else
The murine bone marrow has a central role in immune function and health as the primary source of leukocytes in adult mice. Laboratory mice provide a human-homologous, genetically manipulable and reproducible model that has enabled an immeasurable volume of high-quality immunological research. However, recent research has questioned the translatability of laboratory mouse research into humans and proposed that the exposure of mice to their wild and natural environment may hold the key to further immunological breakthroughs. To date, there have been no studies providing an in-depth cellular analysis of the wild mouse bone marrow. This study utilized wild mice from an isolated island population (Isle of May, Scotland, UK) and performed flow cytometric and histological analysis to characterize the myeloid, lymphoid, hematopoietic progenitor, and adipocyte compartments within the wild mouse bone marrow. We find that, compared to laboratory mouse bone marrow, the wild mouse bone marrow differs in every cell type assessed. Some of the major distinctions include; a smaller B cell compartment with an enriched presence of plasma cells, increased proportions of KLRG1+ CD8+ T cells, diminished CD11b expression in the myeloid lineage and a five-fold enlargement of the eosinophil compartment. We conclude that the wild mouse bone marrow is dramatically distinct from its laboratory counterparts, with multiple phenotypes that to our knowledge have never been observed in laboratory models. Further research into these unique features may uncover novel immunological mechanisms and grant a greater understanding of the role of the immune system in a natural setting.
{"title":"The wild mouse bone marrow has a unique myeloid and lymphoid composition and phenotype.","authors":"Andrew Muir, Alex Bennett, Hannah Smith, Larisa Logunova, Andrew Wolfenden, Jonathan Fenn, Ann E Lowe, Andy Brass, John R Grainger, Joanne E Konkel, Janette E Bradley, Iris Mair, Kathryn J Else","doi":"10.1093/discim/kyad005","DOIUrl":"10.1093/discim/kyad005","url":null,"abstract":"<p><p>The murine bone marrow has a central role in immune function and health as the primary source of leukocytes in adult mice. Laboratory mice provide a human-homologous, genetically manipulable and reproducible model that has enabled an immeasurable volume of high-quality immunological research. However, recent research has questioned the translatability of laboratory mouse research into humans and proposed that the exposure of mice to their wild and natural environment may hold the key to further immunological breakthroughs. To date, there have been no studies providing an in-depth cellular analysis of the wild mouse bone marrow. This study utilized wild mice from an isolated island population (Isle of May, Scotland, UK) and performed flow cytometric and histological analysis to characterize the myeloid, lymphoid, hematopoietic progenitor, and adipocyte compartments within the wild mouse bone marrow. We find that, compared to laboratory mouse bone marrow, the wild mouse bone marrow differs in every cell type assessed. Some of the major distinctions include; a smaller B cell compartment with an enriched presence of plasma cells, increased proportions of KLRG1+ CD8+ T cells, diminished CD11b expression in the myeloid lineage and a five-fold enlargement of the eosinophil compartment. We conclude that the wild mouse bone marrow is dramatically distinct from its laboratory counterparts, with multiple phenotypes that to our knowledge have never been observed in laboratory models. Further research into these unique features may uncover novel immunological mechanisms and grant a greater understanding of the role of the immune system in a natural setting.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44544870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-02-18eCollection Date: 2023-01-01DOI: 10.1093/discim/kyad004
Bethany C Kennedy, Isaac Dean, David R Withers
The clinical success of immune checkpoint blockade in some patients has transformed treatment approaches in cancer and offers the hope of durable curative responses. Building from studies of chronic infection, the composition of tumour infiltrating lymphocytes and in particular, the spectrum of exhausted CD8 T cells has now been characterized in detail, profiling the phenotype, function, transcriptional regulation and even the epigenetic changes. However, what remains less clear is how intratumoural immune cells interface with populations in the periphery, both in terms of sustaining the response in cancer, but also in establishing systemic memory responses that can provide long-term protection. Here we will succinctly review the current understanding of the anti-tumour response, consider the tissue microenvironments that support key cellular subsets and the extent to which cellular migration between these sites impacts the response.
免疫检查点阻断疗法在一些患者身上取得的临床成功改变了癌症的治疗方法,并为持久的治疗反应带来了希望。在慢性感染研究的基础上,肿瘤浸润淋巴细胞的组成,特别是衰竭 CD8 T 细胞的谱系现已得到详细描述,包括表型、功能、转录调控甚至表观遗传学变化。然而,肿瘤内的免疫细胞如何与外周的免疫细胞群相联系,这不仅关系到在癌症中维持反应,还关系到建立可提供长期保护的全身记忆反应,这一点仍然不太清楚。在此,我们将简明扼要地回顾目前对抗肿瘤反应的理解,考虑支持关键细胞亚群的组织微环境,以及细胞在这些部位之间的迁移对反应的影响程度。
{"title":"Migration of stem-like CD8 T cells between tissue microenvironments underpins successful anti-tumour immune responses.","authors":"Bethany C Kennedy, Isaac Dean, David R Withers","doi":"10.1093/discim/kyad004","DOIUrl":"10.1093/discim/kyad004","url":null,"abstract":"<p><p>The clinical success of immune checkpoint blockade in some patients has transformed treatment approaches in cancer and offers the hope of durable curative responses. Building from studies of chronic infection, the composition of tumour infiltrating lymphocytes and in particular, the spectrum of exhausted CD8 T cells has now been characterized in detail, profiling the phenotype, function, transcriptional regulation and even the epigenetic changes. However, what remains less clear is how intratumoural immune cells interface with populations in the periphery, both in terms of sustaining the response in cancer, but also in establishing systemic memory responses that can provide long-term protection. Here we will succinctly review the current understanding of the anti-tumour response, consider the tissue microenvironments that support key cellular subsets and the extent to which cellular migration between these sites impacts the response.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10052398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9235516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-02-07eCollection Date: 2023-01-01DOI: 10.1093/discim/kyad003
Katie J Smith, Giuseppe Sciumè, Shoba Amarnath
Innate lymphoid cells (ILCs) are tissue-resident immune cells that have been recently implicated in initiating and driving anti-tumor responses. ILCs are classified into three main groups, namely type 1 ILCs (ILC1), type 2 ILCs, and type 3 ILCs. All three groups have been implicated in either eliciting pro or anti-tumor immune responses in different cancer subtypes with the consensus that ILCs cannot be overlooked within the field of anti-tumor immune responses. In this review, we will specifically expand on the knowledge on ILC1, their characterization, function, and plasticity in anti-cancer immune responses. Within this premise, we will discuss caveats of ILC1 characterization, and expand on the expression and function of immune checkpoint receptors within ILC1 subsets, specifically focusing on the role of programmed cell death-1 receptor in controlling specific ILC1 responses. We summarize that ILC1s are a vital component in initiating anti-tumor responses and can be boosted by checkpoint receptors.
{"title":"Twenty-One Flavors of Type 1 Innate Lymphoid Cells with PD-1 (Programmed Cell Death-1 Receptor) Sprinkles.","authors":"Katie J Smith, Giuseppe Sciumè, Shoba Amarnath","doi":"10.1093/discim/kyad003","DOIUrl":"10.1093/discim/kyad003","url":null,"abstract":"<p><p>Innate lymphoid cells (ILCs) are tissue-resident immune cells that have been recently implicated in initiating and driving anti-tumor responses. ILCs are classified into three main groups, namely type 1 ILCs (ILC1), type 2 ILCs, and type 3 ILCs. All three groups have been implicated in either eliciting pro or anti-tumor immune responses in different cancer subtypes with the consensus that ILCs cannot be overlooked within the field of anti-tumor immune responses. In this review, we will specifically expand on the knowledge on ILC1, their characterization, function, and plasticity in anti-cancer immune responses. Within this premise, we will discuss caveats of ILC1 characterization, and expand on the expression and function of immune checkpoint receptors within ILC1 subsets, specifically focusing on the role of programmed cell death-1 receptor in controlling specific ILC1 responses. We summarize that ILC1s are a vital component in initiating anti-tumor responses and can be boosted by checkpoint receptors.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49467195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-19eCollection Date: 2023-01-01DOI: 10.1093/discim/kyad002
Jessica Mallaby, William Mwangi, Joseph Ng, Alexander Stewart, Daniel Dorey-Robinson, David Kipling, Uri Hershberg, Franca Fraternali, Venugopal Nair, Deborah Dunn-Walters
Sustainable modern poultry production depends on effective protection against infectious diseases and a diverse range of antibodies is key for an effective immune response. In the domestic chicken, somatic gene conversion is the dominant process in which the antibody immunoglobulin genes are diversified. Affinity maturation by somatic hypermutation (SHM) also occurs, but the relative contribution of gene conversion versus somatic hypermutation to immunoglobulin (Ig) gene diversity is poorly understood. In this study, we use high throughput long-read sequencing to study immunoglobulin diversity in multiple immune-associated tissues in Rhode Island Red chickens. To better understand the impact of genetic diversification in the chicken, a novel gene conversion identification software was developed (BrepConvert). In this study, BrepConvert enabled the identification of over 1 million gene conversion events. Mapping the occurrence of putative somatic gene conversion (SGC) events throughout the variable gene region revealed repetitive and highly restricted patterns of genetic insertions in both the antibody heavy and light chains. These patterns coincided with the locations of genetic variability in available pseudogenes and align with antigen binding sites, predominately the complementary determining regions (CDRs). We found biased usage of pseudogenes during gene conversion, as well as immunoglobulin heavy chain diversity gene (IGHD) preferences during V(D)J gene rearrangement, suggesting that antibody diversification in chickens is more focused than the genetic potential for diversity would suggest.
{"title":"Diversification of immunoglobulin genes by gene conversion in the domestic chicken (<i>Gallus gallus</i> domesticus).","authors":"Jessica Mallaby, William Mwangi, Joseph Ng, Alexander Stewart, Daniel Dorey-Robinson, David Kipling, Uri Hershberg, Franca Fraternali, Venugopal Nair, Deborah Dunn-Walters","doi":"10.1093/discim/kyad002","DOIUrl":"10.1093/discim/kyad002","url":null,"abstract":"<p><p>Sustainable modern poultry production depends on effective protection against infectious diseases and a diverse range of antibodies is key for an effective immune response. In the domestic chicken, somatic gene conversion is the dominant process in which the antibody immunoglobulin genes are diversified. Affinity maturation by somatic hypermutation (SHM) also occurs, but the relative contribution of gene conversion versus somatic hypermutation to immunoglobulin (Ig) gene diversity is poorly understood. In this study, we use high throughput long-read sequencing to study immunoglobulin diversity in multiple immune-associated tissues in Rhode Island Red chickens. To better understand the impact of genetic diversification in the chicken, a novel gene conversion identification software was developed (BrepConvert). In this study, BrepConvert enabled the identification of over 1 million gene conversion events. Mapping the occurrence of putative somatic gene conversion (SGC) events throughout the variable gene region revealed repetitive and highly restricted patterns of genetic insertions in both the antibody heavy and light chains. These patterns coincided with the locations of genetic variability in available pseudogenes and align with antigen binding sites, predominately the complementary determining regions (CDRs). We found biased usage of pseudogenes during gene conversion, as well as immunoglobulin heavy chain diversity gene (IGHD) preferences during V(D)J gene rearrangement, suggesting that antibody diversification in chickens is more focused than the genetic potential for diversity would suggest.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41469775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-18eCollection Date: 2023-01-01DOI: 10.1093/discim/kyad001
Danielle J Smyth, Madeleine P J White, Chris J C Johnston, Anne-Marie Donachie, Marta Campillo Poveda, Henry J McSorley, Rick M Maizels
In animal models of inflammatory colitis, pathology can be ameliorated by several intestinal helminth parasites, including the mouse nematode Heligmosomoides polygyrus. To identify parasite products that may exert anti-inflammatory effects in vivo, we tested H. polygyrus excretory-secretory (HES) products, as well as a recombinantly expressed parasite protein, transforming growth factor mimic (TGM), that functionally mimics the mammalian immunomodulatory cytokine TGF-β. HES and TGM showed a degree of protection in dextran sodium sulphate-induced colitis, with a reduction in inflammatory cytokines, but did not fully block the development of pathology. HES also showed little benefit in a similar acute trinitrobenzene sulphonic acid-induced model. However, in a T cell transfer-mediated model with recombination activation gene (RAG)-deficient mice, HES-reduced disease scores if administered throughout the first 2 or 4 weeks following transfer but was less effective if treatment was delayed until 14 days after T cell transfer. Recombinant TGM similarly dampened colitis in RAG-deficient recipients of effector T cells, and was effective even if introduced only once symptoms had begun to be manifest. These results are a promising indication that TGM may replicate, and even surpass, the modulatory properties of native parasite HES.
在炎症性结肠炎的动物模型中,包括小鼠多角螺旋体线虫在内的几种肠道蠕虫寄生虫可改善病理学。为了找出可能在体内发挥抗炎作用的寄生虫产物,我们测试了多钩吻蛭的排泄-分泌(HES)产物以及一种重组表达的寄生虫蛋白--转化生长因子模拟物(TGM),后者在功能上模拟哺乳动物的免疫调节细胞因子 TGF-β。HES 和 TGM 对葡聚糖硫酸钠诱导的结肠炎有一定程度的保护作用,可减少炎性细胞因子,但并不能完全阻止病变的发展。在类似的急性三硝基苯磺酸诱导模型中,HES 也没有显示出什么益处。然而,在由 T 细胞转移介导的重组活化基因(RAG)缺陷小鼠模型中,如果在 T 细胞转移后的头 2 周或 4 周内给药,HES 可降低疾病评分,但如果延迟到 T 细胞转移后 14 天才给药,则效果较差。重组 TGM 同样能抑制 RAG 缺陷受体效应 T 细胞的结肠炎,而且即使在症状开始显现时才使用也有效。这些结果很有希望地表明,TGM 可能复制甚至超越原生寄生虫 HES 的调节特性。
{"title":"Protection from T cell-dependent colitis by the helminth-derived immunomodulatory mimic of transforming growth factor-β, <i>Hp</i>-TGM.","authors":"Danielle J Smyth, Madeleine P J White, Chris J C Johnston, Anne-Marie Donachie, Marta Campillo Poveda, Henry J McSorley, Rick M Maizels","doi":"10.1093/discim/kyad001","DOIUrl":"10.1093/discim/kyad001","url":null,"abstract":"<p><p>In animal models of inflammatory colitis, pathology can be ameliorated by several intestinal helminth parasites, including the mouse nematode <i>Heligmosomoides polygyrus</i>. To identify parasite products that may exert anti-inflammatory effects <i>in vivo</i>, we tested <i>H. polygyrus</i> excretory-secretory (HES) products, as well as a recombinantly expressed parasite protein, transforming growth factor mimic (TGM), that functionally mimics the mammalian immunomodulatory cytokine TGF-β. HES and TGM showed a degree of protection in dextran sodium sulphate-induced colitis, with a reduction in inflammatory cytokines, but did not fully block the development of pathology. HES also showed little benefit in a similar acute trinitrobenzene sulphonic acid-induced model. However, in a T cell transfer-mediated model with recombination activation gene (RAG)-deficient mice, HES-reduced disease scores if administered throughout the first 2 or 4 weeks following transfer but was less effective if treatment was delayed until 14 days after T cell transfer. Recombinant TGM similarly dampened colitis in RAG-deficient recipients of effector T cells, and was effective even if introduced only once symptoms had begun to be manifest. These results are a promising indication that TGM may replicate, and even surpass, the modulatory properties of native parasite HES.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9958376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9329589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Early symptoms include the loss of memory and mild cognitive ability; however, as the disease progresses, these symptoms can present with increased severity manifesting as mood and behaviour changes, disorientation, and a loss of motor/body control. AD is one of the leading causes of death in the UK, and with an ever-increasing ageing society, patient numbers are predicted to rise posing a significant global health emergency. AD is a complex neurophysiological disorder where pathology is characterized by the deposition and aggregation of misfolded amyloid-beta (Aβ)-protein that in-turn promotes excessive tau-protein production which together drives neuronal cell dysfunction, neuroinflammation, and neurodegeneration. It is widely accepted that AD is driven by a combination of both genetic and immunological processes with recent data suggesting that adaptive immune cell activity within the parenchyma occurs throughout disease. The mechanisms behind these observations remain unclear but suggest that manipulating the adaptive immune response during AD may be an effective therapeutic strategy. Using immunotherapy for AD treatment is not a new concept as the only two approved treatments for AD use antibody-based approaches to target Aβ. However, these have been shown to only temporarily ease symptoms or slow progression highlighting the urgent need for newer treatments. This review discusses the role of the adaptive immune system during AD, how microbial infections may be contributing to inflammatory immune activity and suggests how adaptive immune processes can pose as therapeutic targets for this devastating disease.
{"title":"The association of microbial infection and adaptive immune cell activation in Alzheimer’s Disease","authors":"Mathew Clement","doi":"10.1093/discim/kyad015","DOIUrl":"https://doi.org/10.1093/discim/kyad015","url":null,"abstract":"Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Early symptoms include the loss of memory and mild cognitive ability; however, as the disease progresses, these symptoms can present with increased severity manifesting as mood and behaviour changes, disorientation, and a loss of motor/body control. AD is one of the leading causes of death in the UK, and with an ever-increasing ageing society, patient numbers are predicted to rise posing a significant global health emergency. AD is a complex neurophysiological disorder where pathology is characterized by the deposition and aggregation of misfolded amyloid-beta (Aβ)-protein that in-turn promotes excessive tau-protein production which together drives neuronal cell dysfunction, neuroinflammation, and neurodegeneration. It is widely accepted that AD is driven by a combination of both genetic and immunological processes with recent data suggesting that adaptive immune cell activity within the parenchyma occurs throughout disease. The mechanisms behind these observations remain unclear but suggest that manipulating the adaptive immune response during AD may be an effective therapeutic strategy. Using immunotherapy for AD treatment is not a new concept as the only two approved treatments for AD use antibody-based approaches to target Aβ. However, these have been shown to only temporarily ease symptoms or slow progression highlighting the urgent need for newer treatments. This review discusses the role of the adaptive immune system during AD, how microbial infections may be contributing to inflammatory immune activity and suggests how adaptive immune processes can pose as therapeutic targets for this devastating disease.","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135701444","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}
High endothelial venules (HEVs) are specialized postcapillary venules that specifically serve to recruit circulating lymphocytes to secondary lymphoid organs (SLOs) where cognate antigens can be encountered, and immune responses can be initiated. The presence of HEV-like vessels in primary human solid tumours and their association with lymphocyte infiltration and favourable clinical outcomes and response to immunotherapy have provided a rationale for therapeutically inducing these vessels in tumours for immunotherapeutic benefit. Here we specifically discuss evidence for a link between T-cell activation and development of useful tumour-associated HEV (TA-HEV). We discuss the molecular and functional features of TA-HEV, highlighting the benefits for promoting tumour immunity and the important unanswered questions that need to be addressed before TA-HEV induction can be optimized for immunotherapeutic benefit.
{"title":"The link between T cell activation and development of functionally useful tumour-associated high endothelial venules.","authors":"Stefan Milutinovic, Awen Gallimore","doi":"10.1093/discim/kyad006","DOIUrl":"https://doi.org/10.1093/discim/kyad006","url":null,"abstract":"<p><p>High endothelial venules (HEVs) are specialized postcapillary venules that specifically serve to recruit circulating lymphocytes to secondary lymphoid organs (SLOs) where cognate antigens can be encountered, and immune responses can be initiated. The presence of HEV-like vessels in primary human solid tumours and their association with lymphocyte infiltration and favourable clinical outcomes and response to immunotherapy have provided a rationale for therapeutically inducing these vessels in tumours for immunotherapeutic benefit. Here we specifically discuss evidence for a link between T-cell activation and development of useful tumour-associated HEV (TA-HEV). We discuss the molecular and functional features of TA-HEV, highlighting the benefits for promoting tumour immunity and the important unanswered questions that need to be addressed before TA-HEV induction can be optimized for immunotherapeutic benefit.</p>","PeriodicalId":72830,"journal":{"name":"Discovery immunology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10243744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9652973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}