Pub Date : 2024-09-27DOI: 10.1126/sciimmunol.adj8094
Vladyslav Kavaka, Luisa Mutschler, Clara de la Rosa del Val, Klara Eglseer, Ana M. Gómez Martínez, Andrea Flierl-Hecht, Birgit Ertl-Wagner, Daniel Keeser, Martin Mortazavi, Klaus Seelos, Hanna Zimmermann, Jürgen Haas, Brigitte Wildemann, Tania Kümpfel, Klaus Dornmair, Thomas Korn, Reinhard Hohlfeld, Martin Kerschensteiner, Lisa Ann Gerdes, Eduardo Beltrán
Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8+ T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8+ T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8+ T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS. Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8+ T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease.
多发性硬化症（MS）是中枢神经系统的一种炎症性神经疾病，在神经发炎之前有一个亚临床阶段。CD8 + T细胞在多发性硬化病灶中含量丰富，但它们在疾病病理中的潜在作用仍不清楚。利用高通量单细胞 RNA 测序和单细胞 T 细胞受体分析，我们比较了单卵双生子血液和脑脊液（CSF）中的 CD8 + T 细胞克隆，其中同卵双生子没有神经炎症或有亚临床神经炎症（SCNI）。我们发现了与多发性硬化症相关的外周免疫学和代谢改变，表明迁移性、促炎性和活化的 CD8 + T 细胞表型增强，这在患有 SCNI 的同卵双生子和多发性硬化症患者的独立验证队列中也很明显。总之，我们的深入单细胞分析表明了浸润的 CD8 + T 细胞对疾病的促炎作用，并确定了疾病前驱期和终末期的潜在免疫学和代谢治疗靶点。
{"title":"Twin study identifies early immunological and metabolic dysregulation of CD8+ T cells in multiple sclerosis","authors":"Vladyslav Kavaka, Luisa Mutschler, Clara de la Rosa del Val, Klara Eglseer, Ana M. Gómez Martínez, Andrea Flierl-Hecht, Birgit Ertl-Wagner, Daniel Keeser, Martin Mortazavi, Klaus Seelos, Hanna Zimmermann, Jürgen Haas, Brigitte Wildemann, Tania Kümpfel, Klaus Dornmair, Thomas Korn, Reinhard Hohlfeld, Martin Kerschensteiner, Lisa Ann Gerdes, Eduardo Beltrán","doi":"10.1126/sciimmunol.adj8094","DOIUrl":"10.1126/sciimmunol.adj8094","url":null,"abstract":"<div >Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8<sup>+</sup> T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8<sup>+</sup> T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8<sup>+</sup> T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS. Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8<sup>+</sup> T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adj8094","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1126/sciimmunol.adl3755
Sachin H. Bhagchandani, Leerang Yang, Jonathan H. Lam, Laura Maiorino, Elana Ben-Akiva, Kristen A. Rodrigues, Anna Romanov, Heikyung Suh, Aereas Aung, Shengwei Wu, Anika Wadhera, Arup K. Chakraborty, Darrell J. Irvine
Prolonging exposure to subunit vaccines during the primary immune response enhances humoral immunity. Escalating-dose immunization (EDI), administering vaccines every other day in an increasing pattern over 2 weeks, is particularly effective but challenging to implement clinically. Here, using an HIV Env trimer/saponin adjuvant vaccine, we explored simplified EDI regimens and found that a two-shot regimen administering 20% of the vaccine followed by the remaining 80% of the dose 7 days later increased TFH responses 6-fold, antigen-specific germinal center (GC) B cells 10-fold, and serum antibody titers 10-fold compared with bolus immunization. Computational modeling of TFH priming and the GC response suggested that enhanced activation/antigen loading on dendritic cells and increased capture of antigen delivered in the second dose by follicular dendritic cells contribute to these effects, predictions we verified experimentally. These results suggest that a two-shot priming approach can be used to substantially enhance responses to subunit vaccines.
在初级免疫反应期间延长亚单位疫苗的接种时间可增强体液免疫。递增剂量免疫接种（EDI）是指在两周内以递增的方式隔天接种疫苗，这种方法特别有效，但在临床上实施却很困难。在这里，我们使用一种 HIV Env 三聚体/皂素佐剂疫苗探索了简化的 EDI 方案，并发现与栓剂免疫法相比，先注射 20% 疫苗，7 天后再注射剩余 80% 疫苗的两针方案可使 TFH 反应增加 6 倍，抗原特异性生殖中心 (GC) B 细胞增加 10 倍，血清抗体滴度增加 10 倍。TFH启动和GC反应的计算模型表明，树突状细胞的活化/抗原负载增强以及滤泡树突状细胞对第二剂抗原的捕获增加有助于产生这些效应，我们在实验中验证了这一预测。这些结果表明，两针引物法可以大大提高亚单位疫苗的应答。
{"title":"Two-dose priming immunization amplifies humoral immunity by synchronizing vaccine delivery with the germinal center response","authors":"Sachin H. Bhagchandani, Leerang Yang, Jonathan H. Lam, Laura Maiorino, Elana Ben-Akiva, Kristen A. Rodrigues, Anna Romanov, Heikyung Suh, Aereas Aung, Shengwei Wu, Anika Wadhera, Arup K. Chakraborty, Darrell J. Irvine","doi":"10.1126/sciimmunol.adl3755","DOIUrl":"10.1126/sciimmunol.adl3755","url":null,"abstract":"<div >Prolonging exposure to subunit vaccines during the primary immune response enhances humoral immunity. Escalating-dose immunization (EDI), administering vaccines every other day in an increasing pattern over 2 weeks, is particularly effective but challenging to implement clinically. Here, using an HIV Env trimer/saponin adjuvant vaccine, we explored simplified EDI regimens and found that a two-shot regimen administering 20% of the vaccine followed by the remaining 80% of the dose 7 days later increased T<sub>FH</sub> responses 6-fold, antigen-specific germinal center (GC) B cells 10-fold, and serum antibody titers 10-fold compared with bolus immunization. Computational modeling of T<sub>FH</sub> priming and the GC response suggested that enhanced activation/antigen loading on dendritic cells and increased capture of antigen delivered in the second dose by follicular dendritic cells contribute to these effects, predictions we verified experimentally. These results suggest that a two-shot priming approach can be used to substantially enhance responses to subunit vaccines.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adl3755","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1126/sciimmunol.adp3475
Darren R. Heintzman, Rachael C. Sinard, Emilie L. Fisher, Xiang Ye, Andrew R. Patterson, Joel H. Elasy, Kelsey Voss, Channing Chi, Ayaka Sugiura, Gabriel J. Rodriguez-Garcia, Nowrin U. Chowdhury, Emily N. Arner, Evan S. Krystoviak, Frank M. Mason, Yasmine T. Toudji, KayLee K. Steiner, Wasay Khan, Lana M. Olson, Angela L. Jones, Hanna S. Hong, Lindsay Bass, Katherine L. Beier, Wentao Deng, Costas A. Lyssiotis, Dawn C. Newcomb, Alexander G. Bick, W. Kimryn Rathmell, John T. Wilson, Jeffrey C. Rathmell
Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (TH1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many TH1 cells subjected to such temperatures died, surviving TH1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to TH1 cells. TH1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of TH1 cells to maintain genomic integrity and enhance effector functions.
热是炎症的一个主要特征，但它对免疫细胞的影响仍不确定。我们的研究表明，中度发热温度（39°C）会增加小鼠 CD4 T 细胞的新陈代谢、增殖和炎症效应活性，同时降低调节性 T 细胞的抑制能力。然而，受热的 T 辅助细胞 1（T H 1）会选择性地出现线粒体应激和 DNA 损伤，从而激活 Trp53 和干扰素基因刺激因子通路。虽然在这种温度下许多 T H 1 细胞死亡，但存活下来的 T H 1 细胞线粒体质量增加，活性增强。电子传递链复合物 1（ETC1）在发热范围的温度下迅速受损，这种现象对 T H 1 细胞特别不利。在人类慢性炎症中也检测到 T H 1 细胞的 DNA 损伤和 ETC1 标志升高。因此，发烧相关温度会破坏 ETC1，从而选择性地驱动 T H 1 细胞凋亡或适应，以保持基因组完整性并增强效应功能。
{"title":"Subset-specific mitochondrial stress and DNA damage shape T cell responses to fever and inflammation","authors":"Darren R. Heintzman, Rachael C. Sinard, Emilie L. Fisher, Xiang Ye, Andrew R. Patterson, Joel H. Elasy, Kelsey Voss, Channing Chi, Ayaka Sugiura, Gabriel J. Rodriguez-Garcia, Nowrin U. Chowdhury, Emily N. Arner, Evan S. Krystoviak, Frank M. Mason, Yasmine T. Toudji, KayLee K. Steiner, Wasay Khan, Lana M. Olson, Angela L. Jones, Hanna S. Hong, Lindsay Bass, Katherine L. Beier, Wentao Deng, Costas A. Lyssiotis, Dawn C. Newcomb, Alexander G. Bick, W. Kimryn Rathmell, John T. Wilson, Jeffrey C. Rathmell","doi":"10.1126/sciimmunol.adp3475","DOIUrl":"10.1126/sciimmunol.adp3475","url":null,"abstract":"<div >Heat is a cardinal feature of inflammation, yet its impacts on immune cells remain uncertain. We show that moderate-grade fever temperatures (39°C) increased murine CD4 T cell metabolism, proliferation, and inflammatory effector activity while decreasing regulatory T cell suppressive capacity. However, heat-exposed T helper 1 (T<sub>H</sub>1) cells selectively developed mitochondrial stress and DNA damage that activated Trp53 and stimulator of interferon genes pathways. Although many T<sub>H</sub>1 cells subjected to such temperatures died, surviving T<sub>H</sub>1 cells exhibited increased mitochondrial mass and enhanced activity. Electron transport chain complex 1 (ETC1) was rapidly impaired under fever-range temperatures, a phenomenon that was specifically detrimental to T<sub>H</sub>1 cells. T<sub>H</sub>1 cells with elevated DNA damage and ETC1 signatures were also detected in human chronic inflammation. Thus, fever-relevant temperatures disrupt ETC1 to selectively drive apoptosis or adaptation of T<sub>H</sub>1 cells to maintain genomic integrity and enhance effector functions.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp3475","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1126/sciimmunol.adi3487
Duncan M. Morgan, Brendan L. Horton, Vidit Bhandarkar, Richard Van, Teresa Dinter, Maria Zagorulya, J. Christopher Love, Stefani Spranger
Immune checkpoint blockade (ICB) enhances T cell responses against cancer, leading to long-term survival in a fraction of patients. CD8+ T cell differentiation in response to chronic antigen stimulation is highly complex, and it remains unclear precisely which T cell differentiation states at which anatomic sites are critical for the response to ICB. We identified an intermediate-exhausted population in the white pulp of the spleen that underwent substantial expansion in response to ICB and gave rise to tumor-infiltrating clonotypes. Increased systemic antigen redirected differentiation of this population toward a more circulatory exhausted KLR state, whereas a lack of cross-presented tumor antigen reduced its differentiation in the spleen. An analogous population of exhausted KLR CD8+ T cells in human blood samples exhibited diminished tumor-trafficking ability. Collectively, our data demonstrate the critical role of antigen density within the spleen for the differentiation and expansion of T cell clonotypes in response to ICB.
免疫检查点阻断（ICB）可增强T细胞对癌症的反应，从而使一部分患者长期存活。应对慢性抗原刺激的 CD8+ T 细胞分化非常复杂，目前仍不清楚哪些解剖部位的 T 细胞分化状态对 ICB 的反应至关重要。我们在脾脏白髓中发现了一个中间衰竭群体，它在对 ICB 作出反应时发生了大量扩增，并产生了肿瘤浸润克隆型。全身抗原的增加使这一群体向循环衰竭的 KLR 状态重新分化，而交叉呈现的肿瘤抗原的缺乏则减少了其在脾脏中的分化。人体血液样本中类似的枯竭 KLR CD8+ T 细胞群表现出较低的肿瘤牵引能力。总之，我们的数据证明了脾脏内的抗原密度对 T 细胞克隆型对 ICB 的分化和扩增起着至关重要的作用。
{"title":"Expansion of tumor-reactive CD8+ T cell clonotypes occurs in the spleen in response to immune checkpoint blockade","authors":"Duncan M. Morgan, Brendan L. Horton, Vidit Bhandarkar, Richard Van, Teresa Dinter, Maria Zagorulya, J. Christopher Love, Stefani Spranger","doi":"10.1126/sciimmunol.adi3487","DOIUrl":"10.1126/sciimmunol.adi3487","url":null,"abstract":"<div >Immune checkpoint blockade (ICB) enhances T cell responses against cancer, leading to long-term survival in a fraction of patients. CD8<sup>+</sup> T cell differentiation in response to chronic antigen stimulation is highly complex, and it remains unclear precisely which T cell differentiation states at which anatomic sites are critical for the response to ICB. We identified an intermediate-exhausted population in the white pulp of the spleen that underwent substantial expansion in response to ICB and gave rise to tumor-infiltrating clonotypes. Increased systemic antigen redirected differentiation of this population toward a more circulatory exhausted KLR state, whereas a lack of cross-presented tumor antigen reduced its differentiation in the spleen. An analogous population of exhausted KLR CD8<sup>+</sup> T cells in human blood samples exhibited diminished tumor-trafficking ability. Collectively, our data demonstrate the critical role of antigen density within the spleen for the differentiation and expansion of T cell clonotypes in response to ICB.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1126/sciimmunol.adp6529
Steven P. Wolf, Matthias Leisegang, Madeline Steiner, Veronika Wallace, Kazuma Kiyotani, Yifei Hu, Leonie Rosenberger, Jun Huang, Karin Schreiber, Yusuke Nakamura, Andrea Schietinger, Hans Schreiber
Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4+ T cells (CD4TCRs) from tumor-bearing hosts can be exploited for adoptive TCR therapy. We focused on CD4TCRs targeting an autochthonous mutant neoantigen that is only presented by stroma surrounding the MHC class II–negative cancer cells. The 11 most common tetramer-sorted CD4TCRs were tested using TCR-engineered CD4+ T cells. Three TCRs were characterized by convergent recombination for which multiple T cell clonotypes differed in their nucleotide sequences but encoded identical TCR α and β chains. These preferentially selected TCRs destroyed tumors equally well and halted progression through reprogramming of the tumor stroma. TCRs represented by single T cell clonotypes were similarly effective only if they shared CDR elements with preferentially selected TCRs in both α and β chains. Selecting candidate TCRs on the basis of these characteristics can help identify TCRs that are potentially therapeutically effective.
即使有癌症特异性 T 细胞浸润，癌症最终也会杀死宿主。我们研究了是否可以利用来自肿瘤宿主的 CD4+ T 细胞（CD4TCRs）的癌症特异性 T 细胞受体进行领养 TCR 治疗。我们重点研究了靶向自体突变新抗原的 CD4TCRs，这种新抗原只在 MHC II 类阴性癌细胞周围的基质中出现。使用 TCR 工程化的 CD4+ T 细胞对 11 种最常见的四聚体分选 CD4TCR 进行了测试。有三种 TCR 具有趋同重组的特征，其多个 T 细胞克隆型的核苷酸序列不同，但编码的 TCR α 和 β 链相同。这些优先选择的 TCR 同样能摧毁肿瘤，并通过对肿瘤基质的重编程阻止肿瘤的发展。只有当单个 T 细胞克隆型所代表的 TCR 与优先选择的 TCR 在 α 和 β 链上共享 CDR 元素时，它们才同样有效。根据这些特征选择候选 TCR 有助于识别具有潜在治疗效果的 TCR。
{"title":"CD4+ T cells with convergent TCR recombination reprogram stroma and halt tumor progression in adoptive therapy","authors":"Steven P. Wolf, Matthias Leisegang, Madeline Steiner, Veronika Wallace, Kazuma Kiyotani, Yifei Hu, Leonie Rosenberger, Jun Huang, Karin Schreiber, Yusuke Nakamura, Andrea Schietinger, Hans Schreiber","doi":"10.1126/sciimmunol.adp6529","DOIUrl":"10.1126/sciimmunol.adp6529","url":null,"abstract":"<div >Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4<sup>+</sup> T cells (CD4TCRs) from tumor-bearing hosts can be exploited for adoptive TCR therapy. We focused on CD4TCRs targeting an autochthonous mutant neoantigen that is only presented by stroma surrounding the MHC class II–negative cancer cells. The 11 most common tetramer-sorted CD4TCRs were tested using TCR-engineered CD4<sup>+</sup> T cells. Three TCRs were characterized by convergent recombination for which multiple T cell clonotypes differed in their nucleotide sequences but encoded identical TCR α and β chains. These preferentially selected TCRs destroyed tumors equally well and halted progression through reprogramming of the tumor stroma. TCRs represented by single T cell clonotypes were similarly effective only if they shared CDR elements with preferentially selected TCRs in both α and β chains. Selecting candidate TCRs on the basis of these characteristics can help identify TCRs that are potentially therapeutically effective.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1126/sciimmunol.adn2362
Tobias Kammann, Curtis Cai, Takuya Sekine, Elli Mouchtaridi, Caroline Boulouis, Vera Nilsén, Olga Rivera Ballesteros, Thomas R. Müller, Yu Gao, Elisa J. M. Raineri, Akhirunnesa Mily, Sarah Adamo, Christian Constantz, Julia Niessl, Whitney Weigel, Efthymia Kokkinou, Christopher Stamper, Anne Marchalot, John Bassett, Sabrina Ferreira, Inga Rødahl, Nicole Wild, Demi Brownlie, Chris Tibbitt, Jeffrey Y. W. Mak, David P. Fairlie, Edwin Leeansyah, Jakob Michaelsson, Nicole Marquardt, Jenny Mjösberg, Carl Jorns, Marcus Buggert, Johan K. Sandberg
Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize microbial riboflavin pathway metabolites presented by evolutionarily conserved MR1 molecules. We explored the human MAIT cell compartment across organ donor–matched blood, barrier, and lymphoid tissues. MAIT cell population size was donor dependent with distinct tissue compartmentalization patterns and adaptations: Intestinal CD103+ resident MAIT cells presented an immunoregulatory CD39highCD27low profile, whereas MAIT cells expressing NCAM1/CD56 dominated in the liver and exhibited enhanced effector capacity with elevated response magnitude and polyfunctionality. Both intestinal CD39high and hepatic CD56+ adaptations accumulated with donor age. CD56+ MAIT cells displayed limited T cell receptor–repertoire breadth, elevated MR1 binding, and a transcriptional profile skewed toward innate activation pathways. Furthermore, CD56 was dynamically up-regulated to a persistent steady-state equilibrium after exposure to antigen or IL-7. In summary, we demonstrate functional heterogeneity and tissue site adaptation in resident MAIT cells across human barrier tissues with distinct regulatory and effector signatures.
{"title":"MAIT cell heterogeneity across paired human tissues reveals specialization of distinct regulatory and enhanced effector profiles","authors":"Tobias Kammann, Curtis Cai, Takuya Sekine, Elli Mouchtaridi, Caroline Boulouis, Vera Nilsén, Olga Rivera Ballesteros, Thomas R. Müller, Yu Gao, Elisa J. M. Raineri, Akhirunnesa Mily, Sarah Adamo, Christian Constantz, Julia Niessl, Whitney Weigel, Efthymia Kokkinou, Christopher Stamper, Anne Marchalot, John Bassett, Sabrina Ferreira, Inga Rødahl, Nicole Wild, Demi Brownlie, Chris Tibbitt, Jeffrey Y. W. Mak, David P. Fairlie, Edwin Leeansyah, Jakob Michaelsson, Nicole Marquardt, Jenny Mjösberg, Carl Jorns, Marcus Buggert, Johan K. Sandberg","doi":"10.1126/sciimmunol.adn2362","DOIUrl":"10.1126/sciimmunol.adn2362","url":null,"abstract":"<div >Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize microbial riboflavin pathway metabolites presented by evolutionarily conserved MR1 molecules. We explored the human MAIT cell compartment across organ donor–matched blood, barrier, and lymphoid tissues. MAIT cell population size was donor dependent with distinct tissue compartmentalization patterns and adaptations: Intestinal CD103<sup>+</sup> resident MAIT cells presented an immunoregulatory CD39<sup>high</sup>CD27<sup>low</sup> profile, whereas MAIT cells expressing NCAM1/CD56 dominated in the liver and exhibited enhanced effector capacity with elevated response magnitude and polyfunctionality. Both intestinal CD39<sup>high</sup> and hepatic CD56<sup>+</sup> adaptations accumulated with donor age. CD56<sup>+</sup> MAIT cells displayed limited T cell receptor–repertoire breadth, elevated MR1 binding, and a transcriptional profile skewed toward innate activation pathways. Furthermore, CD56 was dynamically up-regulated to a persistent steady-state equilibrium after exposure to antigen or IL-7. In summary, we demonstrate functional heterogeneity and tissue site adaptation in resident MAIT cells across human barrier tissues with distinct regulatory and effector signatures.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1126/sciimmunol.adm8964
Andrea Vecchione, Joseph C. Devlin, Carley Tasker, Venkat Raman Ramnarayan, Paul Haase, Eva Conde, Devin Srivastava, Gurinder S. Atwal, Pierre Bruhns, Andrew J. Murphy, Matthew A. Sleeman, Andre Limnander, Wei Keat Lim, Seblewongel Asrat, Jamie M. Orengo
Understanding the phenotypic and transcriptional signature of immunoglobulin E (IgE)–producing cells is fundamental to plasma cell (PC) biology and development of therapeutic interventions for allergy. Here, using a mouse model of intranasal house dust mite (HDM) exposure, we showed that short-lived IgE PCs emerge in lung draining lymph nodes (dLNs) during early exposure (<3 weeks) and long-lived IgE PCs accumulate in the bone marrow (BM) with prolonged exposure (>7 weeks). IgE PCs had distinct surface and gene expression profiles in these different tissues compared with other Ig isotypes. IgE BMPCs up-regulated genes associated with prosurvival and BM homing, whereas IgE dLN PCs expressed genes associated with recent class switching and differentiation. IgE PCs also exhibited higher expression of endoplasmic reticulum (ER) stress and protein coding genes and higher antibody secretion rate when compared with IgG1. Overall, this study highlights the unique developmental path and transcriptional signature of short-lived and long-lived IgE PCs.
{"title":"IgE plasma cells are transcriptionally and functionally distinct from other isotypes","authors":"Andrea Vecchione, Joseph C. Devlin, Carley Tasker, Venkat Raman Ramnarayan, Paul Haase, Eva Conde, Devin Srivastava, Gurinder S. Atwal, Pierre Bruhns, Andrew J. Murphy, Matthew A. Sleeman, Andre Limnander, Wei Keat Lim, Seblewongel Asrat, Jamie M. Orengo","doi":"10.1126/sciimmunol.adm8964","DOIUrl":"10.1126/sciimmunol.adm8964","url":null,"abstract":"<div >Understanding the phenotypic and transcriptional signature of immunoglobulin E (IgE)–producing cells is fundamental to plasma cell (PC) biology and development of therapeutic interventions for allergy. Here, using a mouse model of intranasal house dust mite (HDM) exposure, we showed that short-lived IgE PCs emerge in lung draining lymph nodes (dLNs) during early exposure (<3 weeks) and long-lived IgE PCs accumulate in the bone marrow (BM) with prolonged exposure (>7 weeks). IgE PCs had distinct surface and gene expression profiles in these different tissues compared with other Ig isotypes. IgE BMPCs up-regulated genes associated with prosurvival and BM homing, whereas IgE dLN PCs expressed genes associated with recent class switching and differentiation. IgE PCs also exhibited higher expression of endoplasmic reticulum (ER) stress and protein coding genes and higher antibody secretion rate when compared with IgG1. Overall, this study highlights the unique developmental path and transcriptional signature of short-lived and long-lived IgE PCs.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adm8964","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1126/sciimmunol.adp0344
Anna Appios, James Davies, Sofia Sirvent, Stephen Henderson, Sébastien Trzebanski, Johannes Schroth, Morven L. Law, Inês Boal Carvalho, Marlene Magalhaes Pinto, Cyril Carvalho, Howard Yuan-Hao Kan, Shreya Lovlekar, Christina Major, Andres Vallejo, Nigel J. Hall, Michael Ardern-Jones, Zhaoyuan Liu, Florent Ginhoux, Sian M. Henson, Rebecca Gentek, Elaine Emmerson, Steffen Jung, Marta E. Polak, Clare L. Bennett
Langerhans cells (LCs) are distinct among phagocytes, functioning both as embryo-derived, tissue-resident macrophages in skin innervation and repair and as migrating professional antigen-presenting cells, a function classically assigned to dendritic cells (DCs). Here, we demonstrate that both intrinsic and extrinsic factors imprint this dual identity. Using ablation of embryo-derived LCs in the murine adult skin and tracking differentiation of incoming monocyte-derived replacements, we found intrinsic intraepidermal heterogeneity. We observed that ontogenically distinct monocytes give rise to LCs. Within the epidermis, Jagged-dependent activation of Notch signaling, likely within the hair follicle niche, provided an initial site of LC commitment before metabolic adaptation and survival of monocyte-derived LCs. In the human skin, embryo-derived LCs in newborns retained transcriptional evidence of their macrophage origin, but this was superseded by DC-like immune modules after postnatal expansion. Thus, adaptation to adult skin niches replicates conditioning of LC at birth, permitting repair of the embryo-derived LC network.
{"title":"Convergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity","authors":"Anna Appios, James Davies, Sofia Sirvent, Stephen Henderson, Sébastien Trzebanski, Johannes Schroth, Morven L. Law, Inês Boal Carvalho, Marlene Magalhaes Pinto, Cyril Carvalho, Howard Yuan-Hao Kan, Shreya Lovlekar, Christina Major, Andres Vallejo, Nigel J. Hall, Michael Ardern-Jones, Zhaoyuan Liu, Florent Ginhoux, Sian M. Henson, Rebecca Gentek, Elaine Emmerson, Steffen Jung, Marta E. Polak, Clare L. Bennett","doi":"10.1126/sciimmunol.adp0344","DOIUrl":"10.1126/sciimmunol.adp0344","url":null,"abstract":"<div >Langerhans cells (LCs) are distinct among phagocytes, functioning both as embryo-derived, tissue-resident macrophages in skin innervation and repair and as migrating professional antigen-presenting cells, a function classically assigned to dendritic cells (DCs). Here, we demonstrate that both intrinsic and extrinsic factors imprint this dual identity. Using ablation of embryo-derived LCs in the murine adult skin and tracking differentiation of incoming monocyte-derived replacements, we found intrinsic intraepidermal heterogeneity. We observed that ontogenically distinct monocytes give rise to LCs. Within the epidermis, Jagged-dependent activation of Notch signaling, likely within the hair follicle niche, provided an initial site of LC commitment before metabolic adaptation and survival of monocyte-derived LCs. In the human skin, embryo-derived LCs in newborns retained transcriptional evidence of their macrophage origin, but this was superseded by DC-like immune modules after postnatal expansion. Thus, adaptation to adult skin niches replicates conditioning of LC at birth, permitting repair of the embryo-derived LC network.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1126/sciimmunol.ads7640
Fahima Akther, David R. Martinez
Multi-omic analysis deciphers the impact of cell-intrinsic and systemic metabolomes on dengue vaccination immunogenicity.
多组学分析解读细胞内在代谢组和全身代谢组对登革热疫苗免疫原性的影响
{"title":"Pre-vax metabolic clues: Cracking the code to a better dengue vaccine","authors":"Fahima Akther, David R. Martinez","doi":"10.1126/sciimmunol.ads7640","DOIUrl":"10.1126/sciimmunol.ads7640","url":null,"abstract":"<div >Multi-omic analysis deciphers the impact of cell-intrinsic and systemic metabolomes on dengue vaccination immunogenicity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1126/sciimmunol.ads7642
Colleen M. Noviello
IL-10 autoantibodies are detected in two patients with severe inflammatory bowel disease.
在两名严重炎症性肠病患者体内检测到了 IL-10 自身抗体。
{"title":"When a double negative is not a positive: Autoantibodies against IL-10 in patients with inflammatory bowel disease","authors":"Colleen M. Noviello","doi":"10.1126/sciimmunol.ads7642","DOIUrl":"10.1126/sciimmunol.ads7642","url":null,"abstract":"<div >IL-10 autoantibodies are detected in two patients with severe inflammatory bowel disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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