Pub Date : 2024-08-02DOI: 10.1126/sciimmunol.ado1227
Cecilia Ruscitti, Joan Abinet, Pauline Maréchal, Margot Meunier, Constance de Meeûs, Domien Vanneste, Pierre Janssen, Mickael Dourcy, Marc Thiry, Fabrice Bureau, Christoph Schneider, Benedicte Machiels, Andres Hidalgo, Florent Ginhoux, Benjamin G. Dewals, Julien Guiot, Florence Schleich, Mutien-Marie Garigliany, Akeila Bellahcène, Coraline Radermecker, Thomas Marichal
The lung is constantly exposed to airborne pathogens and particles that can cause alveolar damage. Hence, appropriate repair responses are essential for gas exchange and life. Here, we deciphered the spatiotemporal trajectory and function of an atypical population of macrophages after lung injury. Post–influenza A virus (IAV) infection, short-lived monocyte-derived Ly6G-expressing macrophages (Ly6G+ Macs) were recruited to the alveoli of lung perilesional areas. Ly6G+ Macs engulfed immune cells, exhibited a high metabolic potential, and clustered with alveolar type 2 epithelial cells (AT2s) in zones of active epithelial regeneration. Ly6G+ Macs were partially dependent on granulocyte-macrophage colony-stimulating factor and interleukin-4 receptor signaling and were essential for AT2-dependent alveolar regeneration. Similar macrophages were recruited in other models of injury and in the airspaces of lungs from patients with suspected pneumonia. This study identifies perilesional alveolar Ly6G+ Macs as a spatially restricted, short-lived macrophage subset promoting epithelial regeneration postinjury, thus representing an attractive therapeutic target for treating lung damage.
{"title":"Recruited atypical Ly6G+ macrophages license alveolar regeneration after lung injury","authors":"Cecilia Ruscitti, Joan Abinet, Pauline Maréchal, Margot Meunier, Constance de Meeûs, Domien Vanneste, Pierre Janssen, Mickael Dourcy, Marc Thiry, Fabrice Bureau, Christoph Schneider, Benedicte Machiels, Andres Hidalgo, Florent Ginhoux, Benjamin G. Dewals, Julien Guiot, Florence Schleich, Mutien-Marie Garigliany, Akeila Bellahcène, Coraline Radermecker, Thomas Marichal","doi":"10.1126/sciimmunol.ado1227","DOIUrl":"10.1126/sciimmunol.ado1227","url":null,"abstract":"<div >The lung is constantly exposed to airborne pathogens and particles that can cause alveolar damage. Hence, appropriate repair responses are essential for gas exchange and life. Here, we deciphered the spatiotemporal trajectory and function of an atypical population of macrophages after lung injury. Post–influenza A virus (IAV) infection, short-lived monocyte-derived Ly6G-expressing macrophages (Ly6G<sup>+</sup> Macs) were recruited to the alveoli of lung perilesional areas. Ly6G<sup>+</sup> Macs engulfed immune cells, exhibited a high metabolic potential, and clustered with alveolar type 2 epithelial cells (AT2s) in zones of active epithelial regeneration. Ly6G<sup>+</sup> Macs were partially dependent on granulocyte-macrophage colony-stimulating factor and interleukin-4 receptor signaling and were essential for AT2-dependent alveolar regeneration. Similar macrophages were recruited in other models of injury and in the airspaces of lungs from patients with suspected pneumonia. This study identifies perilesional alveolar Ly6G<sup>+</sup> Macs as a spatially restricted, short-lived macrophage subset promoting epithelial regeneration postinjury, thus representing an attractive therapeutic target for treating lung damage.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 98","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879346","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 : 2024-08-02DOI: 10.1126/sciimmunol.adr9661
Rachael A. Clark
Virus and T cell inflammation persist in the tissues of patients with Long Covid.
病毒和 T 细胞炎症持续存在于长 Covid 患者的组织中。
{"title":"Enough already: T cell inflammation and SARS-CoV-2 virus persist in Long Covid","authors":"Rachael A. Clark","doi":"10.1126/sciimmunol.adr9661","DOIUrl":"10.1126/sciimmunol.adr9661","url":null,"abstract":"<div >Virus and T cell inflammation persist in the tissues of patients with Long Covid.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 98","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879344","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 : 2024-08-02DOI: 10.1126/sciimmunol.adq7306
Chrysante S. Iliakis, Andreas Wack
Short-lived repair-promoting macrophages are recruited to foci of lung damage during influenza infection—and they are Ly6G positive (see related Research Article by Ruscitti et al.).
{"title":"Never trust a single myeloid marker: Ly6G on repair-promoting lung macrophages","authors":"Chrysante S. Iliakis, Andreas Wack","doi":"10.1126/sciimmunol.adq7306","DOIUrl":"10.1126/sciimmunol.adq7306","url":null,"abstract":"<div >Short-lived repair-promoting macrophages are recruited to foci of lung damage during influenza infection—and they are Ly6G positive (see related Research Article by Ruscitti <i>et al.</i>).</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 98","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879345","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 : 2024-07-26DOI: 10.1126/sciimmunol.adp1139
K. Maude Ashby, Matouš Vobořil, Oscar C. Salgado, S. Thera Lee, Ryan J. Martinez, Christine H. O’Connor, Elise R. Breed, Shuya Xuan, Charles R. Roll, Saumith Bachigari, Hattie Heiland, Daniel B. Stetson, Sergei V. Kotenko, Kristin A. Hogquist
Type I and III interferons (IFNs) are robustly induced during infections and protect cells against viral infection. Both type I and III IFNs are also produced at low levels in the thymus at steady state; however, their role in T cell development and immune tolerance is unclear. Here, we found that both type I and III IFNs were constitutively produced by a very small number of AIRE+ murine thymic epithelial cells, independent of microbial stimulation. Antigen-presenting cells were highly responsive to thymic IFNs, and IFNs were required for the activation and maturation of thymic type 1 conventional dendritic cells, macrophages, and B cells. Loss of IFN sensing led to reduced regulatory T cell selection, reduced T cell receptor (TCR) repertoire diversity, and enhanced autoreactive T cell responses to self-antigens expressed during peripheral IFN signaling. Thus, constitutive exposure to IFNs in the thymus is required for generating a tolerant and diverse TCR repertoire.
Ⅰ型和Ⅲ型干扰素（IFNs）在感染过程中会被强烈诱导，并保护细胞免受病毒感染。I 型和 III 型 IFNs 也会在胸腺中以低水平稳态产生；然而，它们在 T 细胞发育和免疫耐受中的作用尚不清楚。在这里，我们发现极少数 AIRE+ 小鼠胸腺上皮细胞可持续产生 I 型和 III 型 IFNs，不受微生物刺激的影响。抗原递呈细胞对胸腺 IFN 具有高度反应性，胸腺 1 型常规树突状细胞、巨噬细胞和 B 细胞的活化和成熟都需要 IFN。IFN感应的缺失会导致调节性T细胞选择减少、T细胞受体（TCR）库多样性降低以及对外周IFN信号传导过程中表达的自身抗原的自反应性T细胞反应增强。因此，在胸腺中持续暴露于 IFNs 是产生耐受性和多样性 TCR 复合物的必要条件。
{"title":"Sterile production of interferons in the thymus affects T cell repertoire selection","authors":"K. Maude Ashby, Matouš Vobořil, Oscar C. Salgado, S. Thera Lee, Ryan J. Martinez, Christine H. O’Connor, Elise R. Breed, Shuya Xuan, Charles R. Roll, Saumith Bachigari, Hattie Heiland, Daniel B. Stetson, Sergei V. Kotenko, Kristin A. Hogquist","doi":"10.1126/sciimmunol.adp1139","DOIUrl":"10.1126/sciimmunol.adp1139","url":null,"abstract":"<div >Type I and III interferons (IFNs) are robustly induced during infections and protect cells against viral infection. Both type I and III IFNs are also produced at low levels in the thymus at steady state; however, their role in T cell development and immune tolerance is unclear. Here, we found that both type I and III IFNs were constitutively produced by a very small number of AIRE<sup>+</sup> murine thymic epithelial cells, independent of microbial stimulation. Antigen-presenting cells were highly responsive to thymic IFNs, and IFNs were required for the activation and maturation of thymic type 1 conventional dendritic cells, macrophages, and B cells. Loss of IFN sensing led to reduced regulatory T cell selection, reduced T cell receptor (TCR) repertoire diversity, and enhanced autoreactive T cell responses to self-antigens expressed during peripheral IFN signaling. Thus, constitutive exposure to IFNs in the thymus is required for generating a tolerant and diverse TCR repertoire.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 97","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767306","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 : 2024-07-26DOI: 10.1126/sciimmunol.adk3981
Garett Dunsmore, Wei Guo, Ziyi Li, David Alejandro Bejarano, Rhea Pai, Katharine Yang, Immanuel Kwok, Leonard Tan, Melissa Ng, Carlos De La Calle Fabregat, Aline Yatim, Antoine Bougouin, Kevin Mulder, Jake Thomas, Javiera Villar, Mathilde Bied, Benoit Kloeckner, Charles-Antoine Dutertre, Grégoire Gessain, Svetoslav Chakarov, Zhaoyuan Liu, Jean-Yves Scoazec, Ana-Maria Lennon-Dumenil, Thomas Marichal, Catherine Sautès-Fridman, Wolf Herman Fridman, Ankur Sharma, Bing Su, Andreas Schlitzer, Lai Guan Ng, Camille Blériot, Florent Ginhoux
Tumor-associated macrophages (TAMs) are a heterogeneous population of cells whose phenotypes and functions are shaped by factors that are incompletely understood. Herein, we asked when and where TAMs arise from blood monocytes and how they evolve during tumor development. We initiated pancreatic ductal adenocarcinoma (PDAC) in inducible monocyte fate-mapping mice and combined single-cell transcriptomics and high-dimensional flow cytometry to profile the monocyte-to-TAM transition. We revealed that monocytes differentiate first into a transient intermediate population of TAMs that generates two longer-lived lineages of terminally differentiated TAMs with distinct gene expression profiles, phenotypes, and intratumoral localization. Transcriptome datasets and tumor samples from patients with PDAC evidenced parallel TAM populations in humans and their prognostic associations. These insights will support the design of new therapeutic strategies targeting TAMs in PDAC.
{"title":"Timing and location dictate monocyte fate and their transition to tumor-associated macrophages","authors":"Garett Dunsmore, Wei Guo, Ziyi Li, David Alejandro Bejarano, Rhea Pai, Katharine Yang, Immanuel Kwok, Leonard Tan, Melissa Ng, Carlos De La Calle Fabregat, Aline Yatim, Antoine Bougouin, Kevin Mulder, Jake Thomas, Javiera Villar, Mathilde Bied, Benoit Kloeckner, Charles-Antoine Dutertre, Grégoire Gessain, Svetoslav Chakarov, Zhaoyuan Liu, Jean-Yves Scoazec, Ana-Maria Lennon-Dumenil, Thomas Marichal, Catherine Sautès-Fridman, Wolf Herman Fridman, Ankur Sharma, Bing Su, Andreas Schlitzer, Lai Guan Ng, Camille Blériot, Florent Ginhoux","doi":"10.1126/sciimmunol.adk3981","DOIUrl":"10.1126/sciimmunol.adk3981","url":null,"abstract":"<div >Tumor-associated macrophages (TAMs) are a heterogeneous population of cells whose phenotypes and functions are shaped by factors that are incompletely understood. Herein, we asked when and where TAMs arise from blood monocytes and how they evolve during tumor development. We initiated pancreatic ductal adenocarcinoma (PDAC) in inducible monocyte fate-mapping mice and combined single-cell transcriptomics and high-dimensional flow cytometry to profile the monocyte-to-TAM transition. We revealed that monocytes differentiate first into a transient intermediate population of TAMs that generates two longer-lived lineages of terminally differentiated TAMs with distinct gene expression profiles, phenotypes, and intratumoral localization. Transcriptome datasets and tumor samples from patients with PDAC evidenced parallel TAM populations in humans and their prognostic associations. These insights will support the design of new therapeutic strategies targeting TAMs in PDAC.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 97","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767307","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 : 2024-07-19DOI: 10.1126/sciimmunol.adn6509
Ruchi P. Patel, Guido Ghilardi, Yunlin Zhang, Yi-Hao Chiang, Wei Xie, Puneeth Guruprasad, Ki Hyun Kim, Inkook Chun, Mathew G. Angelos, Raymone Pajarillo, Seok Jae Hong, Yong Gu Lee, Olga Shestova, Carolyn Shaw, Ivan Cohen, Aasha Gupta, Trang Vu, Dean Qian, Steven Yang, Aditya Nimmagadda, Adam E. Snook, Nicholas Siciliano, Antonia Rotolo, Arati Inamdar, Jaryse Harris, Ositadimma Ugwuanyi, Michael Wang, Alberto Carturan, Luca Paruzzo, Linhui Chen, Hatcher J. Ballard, Tatiana Blanchard, Chong Xu, Mohamed Abdel-Mohsen, Khatuna Gabunia, Maria Wysocka, Gerald P. Linette, Beatriz Carreno, David M. Barrett, David T. Teachey, Avery D. Posey, Daniel J. Powell Jr., C. Tor Sauter, Stefano Pileri, Vinodh Pillai, John Scholler, Alain H. Rook, Stephen J. Schuster, Stefan K. Barta, Patrizia Porazzi, Marco Ruella
Most patients treated with US Food and Drug Administration (FDA)–approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.
大多数接受美国食品和药物管理局（FDA）批准的嵌合抗原受体（CAR）T 细胞治疗的患者最终都会出现疾病进展。此外，CAR T 细胞还不能根治预后极差的实体瘤和 T 细胞淋巴瘤等几种血液恶性肿瘤。影响收养 T 细胞免疫疗法临床成功的主要障碍之一是 CAR T 细胞功能障碍以及输注后缺乏扩增和/或持久性。在这项研究中，我们发现 CD5 可抑制 CAR T 细胞的活化，而且使用 CRISPR-Cas9 敲除（KO）CD5 可增强 CAR T 细胞在多种血液病和实体瘤模型中的抗肿瘤效果。从机理上讲，CD5 KO能提高T细胞效应功能，增强细胞毒性、体内扩增和持久性，而且在临床前模型中无明显毒性。这些研究结果表明，CD5 是 T 细胞功能的关键抑制因子，是增强 T 细胞疗法的潜在临床靶点。
{"title":"CD5 deletion enhances the antitumor activity of adoptive T cell therapies","authors":"Ruchi P. Patel, Guido Ghilardi, Yunlin Zhang, Yi-Hao Chiang, Wei Xie, Puneeth Guruprasad, Ki Hyun Kim, Inkook Chun, Mathew G. Angelos, Raymone Pajarillo, Seok Jae Hong, Yong Gu Lee, Olga Shestova, Carolyn Shaw, Ivan Cohen, Aasha Gupta, Trang Vu, Dean Qian, Steven Yang, Aditya Nimmagadda, Adam E. Snook, Nicholas Siciliano, Antonia Rotolo, Arati Inamdar, Jaryse Harris, Ositadimma Ugwuanyi, Michael Wang, Alberto Carturan, Luca Paruzzo, Linhui Chen, Hatcher J. Ballard, Tatiana Blanchard, Chong Xu, Mohamed Abdel-Mohsen, Khatuna Gabunia, Maria Wysocka, Gerald P. Linette, Beatriz Carreno, David M. Barrett, David T. Teachey, Avery D. Posey, Daniel J. Powell Jr., C. Tor Sauter, Stefano Pileri, Vinodh Pillai, John Scholler, Alain H. Rook, Stephen J. Schuster, Stefan K. Barta, Patrizia Porazzi, Marco Ruella","doi":"10.1126/sciimmunol.adn6509","DOIUrl":"10.1126/sciimmunol.adn6509","url":null,"abstract":"<div >Most patients treated with US Food and Drug Administration (FDA)–approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 97","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727766","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 : 2024-07-19DOI: 10.1126/sciimmunol.adl1903
Julie Stockis, Thomas Yip, Julia Moreno-Vicente, Oliver Burton, Youhani Samarakoon, Martijn J. Schuijs, Shwetha Raghunathan, Celine Garcia, Weike Luo, Sarah K. Whiteside, Shaun Png, Charlotte Simpson, Stela Monk, Ashley Sawle, Kelvin Yin, Johanna Barbieri, Panagiotis Papadopoulos, Hannah Wong, Hans-Reimer Rodewald, Timothy Vyse, Andrew N. J. McKenzie, Mark S. Cragg, Matthew Hoare, David R. Withers, Hans Jörg Fehling, Rahul Roychoudhuri, Adrian Liston, Timotheus Y. F. Halim
Regulatory T cells (Tregs) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident Tregs and group 2 innate lymphoid cells (ILC2s); however, how Tregs locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of Treg function. Using spatial, cellular, and molecular profiling of the type 2 inflamed niche, we found that ILC2s and Tregs engage in a direct (OX40L-OX40) and chemotaxis-dependent (CCL1-CCR8) cellular dialogue that enforces the local accumulation of Gata3high Tregs, which are transcriptionally and functionally adapted to the type 2 environment. Genetic interruption of ILC2-Treg communication resulted in uncontrolled type 2 lung inflammation after allergen exposure. Mechanistically, we found that Gata3high Tregs can modulate the local bioavailability of the costimulatory molecule OX40L, which subsequently controlled effector memory T helper 2 cell numbers. Hence, ILC2-Treg interactions represent a critical feedback mechanism to control adaptive type 2 immunity.
{"title":"Cross-talk between ILC2 and Gata3high Tregs locally constrains adaptive type 2 immunity","authors":"Julie Stockis, Thomas Yip, Julia Moreno-Vicente, Oliver Burton, Youhani Samarakoon, Martijn J. Schuijs, Shwetha Raghunathan, Celine Garcia, Weike Luo, Sarah K. Whiteside, Shaun Png, Charlotte Simpson, Stela Monk, Ashley Sawle, Kelvin Yin, Johanna Barbieri, Panagiotis Papadopoulos, Hannah Wong, Hans-Reimer Rodewald, Timothy Vyse, Andrew N. J. McKenzie, Mark S. Cragg, Matthew Hoare, David R. Withers, Hans Jörg Fehling, Rahul Roychoudhuri, Adrian Liston, Timotheus Y. F. Halim","doi":"10.1126/sciimmunol.adl1903","DOIUrl":"10.1126/sciimmunol.adl1903","url":null,"abstract":"<div >Regulatory T cells (T<sub>regs</sub>) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident T<sub>regs</sub> and group 2 innate lymphoid cells (ILC2s); however, how T<sub>regs</sub> locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of T<sub>reg</sub> function. Using spatial, cellular, and molecular profiling of the type 2 inflamed niche, we found that ILC2s and T<sub>regs</sub> engage in a direct (OX40L-OX40) and chemotaxis-dependent (CCL1-CCR8) cellular dialogue that enforces the local accumulation of Gata3<sup>high</sup> T<sub>regs</sub>, which are transcriptionally and functionally adapted to the type 2 environment. Genetic interruption of ILC2-T<sub>reg</sub> communication resulted in uncontrolled type 2 lung inflammation after allergen exposure. Mechanistically, we found that Gata3<sup>high</sup> T<sub>regs</sub> can modulate the local bioavailability of the costimulatory molecule OX40L, which subsequently controlled effector memory T helper 2 cell numbers. Hence, ILC2-T<sub>reg</sub> interactions represent a critical feedback mechanism to control adaptive type 2 immunity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 97","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727767","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 : 2024-07-12DOI: 10.1126/sciimmunol.ado5295
Alexander J. Brown, Janice White, Laura Shaw, Jimmy Gross, Andrei Slabodkin, Ella Kushner, Victor Greiff, Jennifer Matsuda, Laurent Gapin, James Scott-Browne, John Kappler, Philippa Marrack
αβ T cell receptor (TCR) V(D)J genes code for billions of TCR combinations. However, only some appear on peripheral T cells in any individual because, to mature, thymocytes must react with low affinity but not high affinity with thymus expressed major histocompatibility (MHC)/peptides. MHC proteins are very polymorphic. Different alleles bind different peptides. Therefore, any individual might express many different MHC alleles to ensure that some peptides from an invader are bound to MHC and activate T cells. However, most individuals express limited numbers of MHC alleles. To explore this, we compared the TCR repertoires of naïve CD4 T cells in mice expressing one or two MHC alleles. Unexpectedly, the TCRs in heterozygotes were less diverse that those in the sum of their MHC homozygous relatives. Our results suggest that thymus negative selection cancels out the advantages of increased thymic positive selection in the MHC heterozygotes.
αβ T 细胞受体（TCR）V(D)J 基因编码数十亿种 TCR 组合。然而，在任何个体的外周 T 细胞中，只有一部分会出现，因为胸腺细胞要成熟，必须与胸腺表达的主要组织相容性（MHC）/肽发生低亲和力而非高亲和力的反应。MHC 蛋白具有很强的多态性。不同的等位基因结合不同的肽。因此，任何个体都可能表达许多不同的 MHC 等位基因，以确保入侵者的某些肽与 MHC 结合并激活 T 细胞。然而，大多数个体表达的 MHC 等位基因数量有限。为了探究这个问题，我们比较了表达一种或两种 MHC 等位基因的小鼠的幼稚 CD4 T 细胞的 TCR 重排。出乎意料的是，杂合子小鼠的 TCR 种类少于其 MHC 等位基因亲属的 TCR 种类总和。我们的研究结果表明，胸腺负选择抵消了MHC杂合子中胸腺正选择增加的优势。
{"title":"MHC heterozygosity limits T cell receptor variability in CD4 T cells","authors":"Alexander J. Brown, Janice White, Laura Shaw, Jimmy Gross, Andrei Slabodkin, Ella Kushner, Victor Greiff, Jennifer Matsuda, Laurent Gapin, James Scott-Browne, John Kappler, Philippa Marrack","doi":"10.1126/sciimmunol.ado5295","DOIUrl":"10.1126/sciimmunol.ado5295","url":null,"abstract":"<div >αβ T cell receptor (TCR) V(D)J genes code for billions of TCR combinations. However, only some appear on peripheral T cells in any individual because, to mature, thymocytes must react with low affinity but not high affinity with thymus expressed major histocompatibility (MHC)/peptides. MHC proteins are very polymorphic. Different alleles bind different peptides. Therefore, any individual might express many different MHC alleles to ensure that some peptides from an invader are bound to MHC and activate T cells. However, most individuals express limited numbers of MHC alleles. To explore this, we compared the TCR repertoires of naïve CD4 T cells in mice expressing one or two MHC alleles. Unexpectedly, the TCRs in heterozygotes were less diverse that those in the sum of their MHC homozygous relatives. Our results suggest that thymus negative selection cancels out the advantages of increased thymic positive selection in the MHC heterozygotes.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 97","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601727","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 : 2024-07-12DOI: 10.1126/sciimmunol.adm7908
Shuo Yang, Meijie Tian, Yulong Dai, Rong Wang, Shigehiro Yamada, Shengyong Feng, Yunyun Wang, Deepak Chhangani, Tiffany Ou, Wenle Li, Xuan Guo, Jennifer McAdow, Diego E. Rincon-Limas, Xin Yin, Wanbo Tai, Gong Cheng, Aaron Johnson
Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.
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