Pub Date : 2025-02-04DOI: 10.1016/j.immuni.2025.01.009
William A. Nyberg, Charlotte H. Wang, Jonathan Ark, Chang Liu, Sylvanie Clouden, Anita Qualls, Sofia Caryotakis, Elina Wells, Katherine Simon, Celeste Garza, Pierre-Louis Bernard, Maya Lopez-Ichikawa, Zhongmei Li, Jin Seo, Gabriella R. Kimmerly, Joseph J. Muldoon, Peixin Amy Chen, Mingcheng Li, Hong-Erh Liang, Kelly Kersten, Justin Eyquem
Genetic engineering of T cells in mouse models is essential for investigating immune mechanisms. We aimed to develop an approach to manipulate T cells in vivo using an evolved adeno-associated virus (AAV) capsid named Ark313. Delivery of a transient transgene expression cassette was feasible using Ark313, and this serotype outperformed natural serotypes. A single intravenous injection of a Cre recombinase-expressing Ark313 in the Ai9 fluorescent reporter mouse model achieved permanent genetic modifications of T cells. Ark313 facilitated in vivo gene editing in both tissue-resident and splenic T cells and validation of immunotherapy targets in solid tumor models. Ark313 delivered large DNA donor templates to T cells in vivo and integrated transgenes in primary CD4+ and CD8+ T cells, including naive T cells. Ark313-mediated transgene delivery presents an efficient approach to target mouse T cells in vivo and a resource for the interrogation of T cell biology and for immunotherapy applications.
{"title":"In vivo engineering of murine T cells using the evolved adeno-associated virus variant Ark313","authors":"William A. Nyberg, Charlotte H. Wang, Jonathan Ark, Chang Liu, Sylvanie Clouden, Anita Qualls, Sofia Caryotakis, Elina Wells, Katherine Simon, Celeste Garza, Pierre-Louis Bernard, Maya Lopez-Ichikawa, Zhongmei Li, Jin Seo, Gabriella R. Kimmerly, Joseph J. Muldoon, Peixin Amy Chen, Mingcheng Li, Hong-Erh Liang, Kelly Kersten, Justin Eyquem","doi":"10.1016/j.immuni.2025.01.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.01.009","url":null,"abstract":"Genetic engineering of T cells in mouse models is essential for investigating immune mechanisms. We aimed to develop an approach to manipulate T cells <em>in vivo</em> using an evolved adeno-associated virus (AAV) capsid named Ark313. Delivery of a transient transgene expression cassette was feasible using Ark313, and this serotype outperformed natural serotypes. A single intravenous injection of a Cre recombinase-expressing Ark313 in the Ai9 fluorescent reporter mouse model achieved permanent genetic modifications of T cells. Ark313 facilitated <em>in vivo</em> gene editing in both tissue-resident and splenic T cells and validation of immunotherapy targets in solid tumor models. Ark313 delivered large DNA donor templates to T cells <em>in vivo</em> and integrated transgenes in primary CD4<sup>+</sup> and CD8<sup>+</sup> T cells, including naive T cells. Ark313-mediated transgene delivery presents an efficient approach to target mouse T cells <em>in vivo</em> and a resource for the interrogation of T cell biology and for immunotherapy applications.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"39 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083705","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 : 2025-02-04DOI: 10.1016/j.immuni.2025.01.010
M. Gordon Joyce, Wei Bu, Wei-Hung Chen, Rebecca A. Gillespie, Sarah F. Andrews, Adam K. Wheatley, Yaroslav Tsybovsky, Jaime L. Jensen, Tyler Stephens, Madhu Prabhakaran, Brian E. Fisher, Sandeep R. Narpala, Meghna Bagchi, Adrian B. McDermott, Gary J. Nabel, Peter D. Kwong, John R. Mascola, Jeffrey I. Cohen, Masaru Kanekiyo
Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with malignancies in humans. Viral infection of B cells is initiated by the viral glycoprotein 350 (gp350) binding to complement receptor 2 (CR2). Despite decades of effort, no vaccines or curative agents have been developed, partly due to lack of atomic-level understanding of the virus-host interface. Here, we determined the 1.7 Å structure of gp350 in complex with CR2. CR2 binding of gp350 utilized the same set of Arg residues required for recognition of its natural ligand, complement C3d. We further determined the structures of gp350 in complex with three potently neutralizing antibodies (nAbs) obtained from vaccinated macaques and EBV-infected individuals. Like the CR2 interaction, these nAbs targeted the acidic pocket within the CR2-binding site on gp350 using Arg residues. Our results illustrate two axes of molecular mimicry—gp350 versus C3d and CR2 versus EBV nAbs—offering insights for EBV vaccines and therapeutics development.
{"title":"Structural basis for complement receptor engagement and virus neutralization through Epstein-Barr virus gp350","authors":"M. Gordon Joyce, Wei Bu, Wei-Hung Chen, Rebecca A. Gillespie, Sarah F. Andrews, Adam K. Wheatley, Yaroslav Tsybovsky, Jaime L. Jensen, Tyler Stephens, Madhu Prabhakaran, Brian E. Fisher, Sandeep R. Narpala, Meghna Bagchi, Adrian B. McDermott, Gary J. Nabel, Peter D. Kwong, John R. Mascola, Jeffrey I. Cohen, Masaru Kanekiyo","doi":"10.1016/j.immuni.2025.01.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.01.010","url":null,"abstract":"Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with malignancies in humans. Viral infection of B cells is initiated by the viral glycoprotein 350 (gp350) binding to complement receptor 2 (CR2). Despite decades of effort, no vaccines or curative agents have been developed, partly due to lack of atomic-level understanding of the virus-host interface. Here, we determined the 1.7 Å structure of gp350 in complex with CR2. CR2 binding of gp350 utilized the same set of Arg residues required for recognition of its natural ligand, complement C3d. We further determined the structures of gp350 in complex with three potently neutralizing antibodies (nAbs) obtained from vaccinated macaques and EBV-infected individuals. Like the CR2 interaction, these nAbs targeted the acidic pocket within the CR2-binding site on gp350 using Arg residues. Our results illustrate two axes of molecular mimicry—gp350 versus C3d and CR2 versus EBV nAbs—offering insights for EBV vaccines and therapeutics development.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"133 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143084095","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 : 2025-02-04DOI: 10.1016/j.immuni.2025.01.013
Nikolai P. Jaschke, Andrew Wang
As a highly diverse and mobile organ, the immune system is uniquely equipped to participate in tissue responses in a tunable manner, depending on the number, type, and nature of cells deployed to the respective organ. Most acute organismal stressors that threaten survival—predation, infection, poisoning, and others—induce pronounced redistribution of immune cells across tissue compartments. Here, we review the current understanding of leukocyte compartmentalization under homeostatic and noxious conditions. We argue that leukocyte shuttling between compartments is a function of local tissue demands, which are linked to the organ’s contribution to adaptive physiology at steady state and upon challenge. We highlight the neuroendocrine signals that relay and organize this trafficking behavior and outline mechanisms underlying the functional diversification of leukocyte responses. In this context, we discuss important areas of future inquiry and the implications of this scientific space for clinical medicine in the era of targeted immunomodulation.
{"title":"Integrated control of leukocyte compartments as a feature of adaptive physiology","authors":"Nikolai P. Jaschke, Andrew Wang","doi":"10.1016/j.immuni.2025.01.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.01.013","url":null,"abstract":"As a highly diverse and mobile organ, the immune system is uniquely equipped to participate in tissue responses in a tunable manner, depending on the number, type, and nature of cells deployed to the respective organ. Most acute organismal stressors that threaten survival—predation, infection, poisoning, and others—induce pronounced redistribution of immune cells across tissue compartments. Here, we review the current understanding of leukocyte compartmentalization under homeostatic and noxious conditions. We argue that leukocyte shuttling between compartments is a function of local tissue demands, which are linked to the organ’s contribution to adaptive physiology at steady state and upon challenge. We highlight the neuroendocrine signals that relay and organize this trafficking behavior and outline mechanisms underlying the functional diversification of leukocyte responses. In this context, we discuss important areas of future inquiry and the implications of this scientific space for clinical medicine in the era of targeted immunomodulation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"7 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083704","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 : 2025-02-03DOI: 10.1016/j.immuni.2025.01.007
Róisín M. McManus, Max P. Komes, Angelika Griep, Francesco Santarelli, Stephanie Schwartz, Juan Ramón Perea, Johannes C.M. Schlachetzki, David S. Bouvier, Michelle-Amirah Khalil, Mario A. Lauterbach, Lea Heinemann, Titus Schlüter, Mehran Shaban Pour, Marta Lovotti, Rainer Stahl, Fraser Duthie, Juan F. Rodríguez-Alcázar, Susanne V. Schmidt, Jasper Spitzer, Peri Noori, Michael T. Heneka
Activation of the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer’s disease (AD) via the release of IL-1β and ASC specks. However, whether NLRP3 is involved in pathways beyond this remained unknown. Here, we found that Aβ deposition in vivo directly triggered NLRP3 activation in APP/PS1 mice, which model many features of AD. Loss of NLRP3 increased glutamine- and glutamate-related metabolism and increased expression of microglial Slc1a3, which was associated with enhanced mitochondrial and metabolic activity. The generation of α-ketoglutarate during this process impacted cellular function, including increased clearance of Aβ peptides as well as epigenetic and gene transcription changes. This pathway was conserved between murine and human cells. Critically, we could mimic this effect pharmacologically using NLRP3-specific inhibitors, but only with chronic NLRP3 inhibition. Together, these data demonstrate an additional role for NLRP3, where it can modulate mitochondrial and metabolic function, with important downstream consequences for the progression of AD.
{"title":"NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer’s disease progression","authors":"Róisín M. McManus, Max P. Komes, Angelika Griep, Francesco Santarelli, Stephanie Schwartz, Juan Ramón Perea, Johannes C.M. Schlachetzki, David S. Bouvier, Michelle-Amirah Khalil, Mario A. Lauterbach, Lea Heinemann, Titus Schlüter, Mehran Shaban Pour, Marta Lovotti, Rainer Stahl, Fraser Duthie, Juan F. Rodríguez-Alcázar, Susanne V. Schmidt, Jasper Spitzer, Peri Noori, Michael T. Heneka","doi":"10.1016/j.immuni.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.01.007","url":null,"abstract":"Activation of the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer’s disease (AD) via the release of IL-1β and ASC specks. However, whether NLRP3 is involved in pathways beyond this remained unknown. Here, we found that Aβ deposition <em>in vivo</em> directly triggered NLRP3 activation in APP/PS1 mice, which model many features of AD. Loss of NLRP3 increased glutamine- and glutamate-related metabolism and increased expression of microglial <em>Slc1a3</em>, which was associated with enhanced mitochondrial and metabolic activity. The generation of α-ketoglutarate during this process impacted cellular function, including increased clearance of Aβ peptides as well as epigenetic and gene transcription changes. This pathway was conserved between murine and human cells. Critically, we could mimic this effect pharmacologically using NLRP3-specific inhibitors, but only with chronic NLRP3 inhibition. Together, these data demonstrate an additional role for NLRP3, where it can modulate mitochondrial and metabolic function, with important downstream consequences for the progression of AD.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"52 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077291","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 : 2025-01-31DOI: 10.1016/j.immuni.2025.01.006
Andri L. Lemarquis, Anastasia I. Kousa, Kimon V. Argyropoulos, Lorenz Jahn, Brianna Gipson, Jonah Pierce, Lucia Serrano-Marin, Kristen Victor, Yuzuka Kanno, Narina N. Girotra, Hana Andrlova, Jennifer Tsai, Enrico Velardi, Roshan Sharma, Simon Grassmann, Olov Ekwall, Andrew B. Goldstone, Jarrod A. Dudakov, Susan DeWolf, Marcel R.M. van den Brink
Thymic injury associated with disease or cancer treatment reduces T cell production and makes patients more vulnerable to infections and cancers. Here, we examined the role of regulatory T (Treg) cells on thymic regeneration. Treg cell frequencies increased in the thymus in various acute injury models. Depletion of Treg cells impaired thymic regeneration, impacting both the thymocyte compartment and the stromal cell compartment; adoptive transfer of Treg cells enhanced regeneration. Expansion of circulating Treg cells, as opposed to that of tissue resident or recent thymic emigrants, explained this increase, as seen using parabiotic and adoptive transfer models. Single-cell analyses of recirculating Treg cells revealed expression of various regenerative factors, including the cytokine amphiregulin. Deletion of amphiregulin in these Treg cells impaired regeneration in the injured thymus. We identified an analogous population of CD39+ICOS+ Treg cells in the human thymus. Our findings point to potential therapeutic avenues to address aging- and treatment-induced immunosuppression.
{"title":"Recirculating regulatory T cells mediate thymic regeneration through amphiregulin following damage","authors":"Andri L. Lemarquis, Anastasia I. Kousa, Kimon V. Argyropoulos, Lorenz Jahn, Brianna Gipson, Jonah Pierce, Lucia Serrano-Marin, Kristen Victor, Yuzuka Kanno, Narina N. Girotra, Hana Andrlova, Jennifer Tsai, Enrico Velardi, Roshan Sharma, Simon Grassmann, Olov Ekwall, Andrew B. Goldstone, Jarrod A. Dudakov, Susan DeWolf, Marcel R.M. van den Brink","doi":"10.1016/j.immuni.2025.01.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.01.006","url":null,"abstract":"Thymic injury associated with disease or cancer treatment reduces T cell production and makes patients more vulnerable to infections and cancers. Here, we examined the role of regulatory T (Treg) cells on thymic regeneration. Treg cell frequencies increased in the thymus in various acute injury models. Depletion of Treg cells impaired thymic regeneration, impacting both the thymocyte compartment and the stromal cell compartment; adoptive transfer of Treg cells enhanced regeneration. Expansion of circulating Treg cells, as opposed to that of tissue resident or recent thymic emigrants, explained this increase, as seen using parabiotic and adoptive transfer models. Single-cell analyses of recirculating Treg cells revealed expression of various regenerative factors, including the cytokine amphiregulin. Deletion of amphiregulin in these Treg cells impaired regeneration in the injured thymus. We identified an analogous population of CD39<sup>+</sup>ICOS<sup>+</sup> Treg cells in the human thymus. Our findings point to potential therapeutic avenues to address aging- and treatment-induced immunosuppression.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"15 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071405","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 : 2025-01-30DOI: 10.1016/j.immuni.2025.01.008
Zhuldyz Zhanzak, Aileen C. Johnson, Petra Foster, Maria A. Cardenas, Anna B. Morris, Joan Zhang, Geeta Karadkhele, I. Raul Badell, Alanna A. Morris, Byron B. Au-Yeung, Fernanda M. Roversi, Juliete A.F. Silva, Cynthia Breeden, Annette Hadley, Weiwen Zhang, Christian P. Larsen, Haydn T. Kissick
Antibodies against the donor human leukocyte antigen (HLA) molecules drive late transplant failure, with HLA-DQ donor-specific antibodies (DSAs) posing the highest rejection risk. Here, we investigated the role of indirect CD4+ T cell epitopes—donor-derived peptides presented by recipient major histocompatibility complex (MHC) class II—in DSA formation. Antigen mapping of samples from HLA-DQ DSA-positive kidney and heart transplant recipients revealed two polymorphic hotspots in donor HLA-DQ that generated alloreactive peptides. Antigen mapping of indirect CD4+ T cell epitopes in a mouse model of fully MHC mismatched skin graft transplantation (BALB/c to C57BL/6) identified a similar epitope (amino acids 287–301) derived from the donor H2-Kd. Tetramer-binding Kd287+ CD4+ T cells were detected during rejection and their transfer into T cell-deficient mice induced DSA. Systemic delivery of high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the frequencies of Kd287+ CD4+ T cells and DSA formation. Thus, targeting a narrow range of donor antigens may prevent DSA formation and improve transplant outcomes.
{"title":"Identification of indirect CD4+ T cell epitopes associated with transplant rejection provides a target for donor-specific tolerance induction","authors":"Zhuldyz Zhanzak, Aileen C. Johnson, Petra Foster, Maria A. Cardenas, Anna B. Morris, Joan Zhang, Geeta Karadkhele, I. Raul Badell, Alanna A. Morris, Byron B. Au-Yeung, Fernanda M. Roversi, Juliete A.F. Silva, Cynthia Breeden, Annette Hadley, Weiwen Zhang, Christian P. Larsen, Haydn T. Kissick","doi":"10.1016/j.immuni.2025.01.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.01.008","url":null,"abstract":"Antibodies against the donor human leukocyte antigen (HLA) molecules drive late transplant failure, with HLA-DQ donor-specific antibodies (DSAs) posing the highest rejection risk. Here, we investigated the role of indirect CD4<sup>+</sup> T cell epitopes—donor-derived peptides presented by recipient major histocompatibility complex (MHC) class II—in DSA formation. Antigen mapping of samples from HLA-DQ DSA-positive kidney and heart transplant recipients revealed two polymorphic hotspots in donor HLA-DQ that generated alloreactive peptides. Antigen mapping of indirect CD4<sup>+</sup> T cell epitopes in a mouse model of fully MHC mismatched skin graft transplantation (BALB/c to C57BL/6) identified a similar epitope (amino acids 287–301) derived from the donor H2-Kd. Tetramer-binding Kd287<sup>+</sup> CD4<sup>+</sup> T cells were detected during rejection and their transfer into T cell-deficient mice induced DSA. Systemic delivery of high-dose donor H2-Kd peptides combined with CTLA4-Ig reduced the frequencies of Kd287<sup>+</sup> CD4<sup>+</sup> T cells and DSA formation. Thus, targeting a narrow range of donor antigens may prevent DSA formation and improve transplant outcomes.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"36 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056437","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}
Emerging studies reveal that neurotransmitters and neuropeptides play critical roles in regulating anti-helminth immune responses, hinting at the potential of intrinsic enteric neurons (iENs) in orchestrating intestinal immunity. Whether and how iENs are activated during infection and the potential neuroimmune interactions involved remain poorly defined. Here, we found that helminth infection activated a subset of iENs. Single-nucleus RNA sequencing (snRNA-seq) of iENs revealed alterations in the transcriptional profile of interleukin (IL)-13R+ intrinsic primary afferent neurons (IPANs), including the upregulation of the neuropeptide β-calcitonin gene-related peptide (CGRP). Using genetic mouse models and engineered viral tools, we demonstrated that group 2 innate lymphoid cell (ILC2)-derived IL-13 was required to activate iENs via the IL-13R, leading to iEN production of β-CGRP, which subsequently inhibited ILC2 responses and anti-helminth immunity. Together, these results reveal a previously unrecognized bi-directional neuroimmune crosstalk in the intestine between a subset of iENs and ILC2s, which influences pathogen clearance.
{"title":"Bi-directional communication between intrinsic enteric neurons and ILC2s inhibits host defense against helminth infection","authors":"Yinsheng Wang, Xiaoyu Zhang, Shaorui Liu, Zhijie Gu, Zijia Sun, Yang Zang, Xiaobao Huang, Yi Wang, Qiang Wang, Qingxia Lin, Ruichao Liu, Suhua Sun, Hongkai Xu, Jiali Wang, Tao Wu, Yan Wang, Yu Li, Hui Li, Zirun Tang, Yifan Qu, Coco Chu","doi":"10.1016/j.immuni.2025.01.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.01.004","url":null,"abstract":"Emerging studies reveal that neurotransmitters and neuropeptides play critical roles in regulating anti-helminth immune responses, hinting at the potential of intrinsic enteric neurons (iENs) in orchestrating intestinal immunity. Whether and how iENs are activated during infection and the potential neuroimmune interactions involved remain poorly defined. Here, we found that helminth infection activated a subset of iENs. Single-nucleus RNA sequencing (snRNA-seq) of iENs revealed alterations in the transcriptional profile of interleukin (IL)-13R<sup>+</sup> intrinsic primary afferent neurons (IPANs), including the upregulation of the neuropeptide β-calcitonin gene-related peptide (CGRP). Using genetic mouse models and engineered viral tools, we demonstrated that group 2 innate lymphoid cell (ILC2)-derived IL-13 was required to activate iENs via the IL-13R, leading to iEN production of β-CGRP, which subsequently inhibited ILC2 responses and anti-helminth immunity. Together, these results reveal a previously unrecognized bi-directional neuroimmune crosstalk in the intestine between a subset of iENs and ILC2s, which influences pathogen clearance.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"53 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056436","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 : 2025-01-28DOI: 10.1016/j.immuni.2025.01.003
Yaw Asare, Guangyao Yan, Christina Schlegl, Matthias Prestel, Emiel P.C. van der Vorst, Abraham J.P. Teunissen, Arailym Aronova, Federica Tosato, Nawraa Naser, Julio Caputo, Geoffrey Prevot, Anthony Azzun, Benedikt Wefers, Wolfgang Wurst, Melanie Schneider, Ignasi Forne, Kiril Bidzhekov, Ronald Naumann, Sander W. van der Laan, Markus Brandhofer, Martin Dichgans
Common genetic variants in a conserved cis-regulatory element (CRE) at histone deacetylase (HDAC)9 are a major risk factor for cardiovascular disease, including stroke and coronary artery disease. Given the consistency of this association and its proinflammatory properties, we examined the mechanisms whereby HDAC9 regulates vascular inflammation. HDAC9 bound and mediated deacetylation of NLRP3 in the NACHT and LRR domains leading to inflammasome activation and lytic cell death. Targeted deletion of the critical CRE in mice increased Hdac9 expression in myeloid cells to exacerbate inflammasome-dependent chronic inflammation. In human carotid endarterectomy samples, increased HDAC9 expression was associated with atheroprogression and clinical plaque instability. Incorporation of TMP195, a class IIa HDAC inhibitor, into lipoprotein-based nanoparticles to target HDAC9 at the site of myeloid-driven vascular inflammation stabilized atherosclerotic plaques, implying a lower risk of plaque rupture and cardiovascular events. Our findings link HDAC9 to atherogenic inflammation and provide a paradigm for anti-inflammatory therapeutics for atherosclerosis.
{"title":"A cis-regulatory element controls expression of histone deacetylase 9 to fine-tune inflammasome-dependent chronic inflammation in atherosclerosis","authors":"Yaw Asare, Guangyao Yan, Christina Schlegl, Matthias Prestel, Emiel P.C. van der Vorst, Abraham J.P. Teunissen, Arailym Aronova, Federica Tosato, Nawraa Naser, Julio Caputo, Geoffrey Prevot, Anthony Azzun, Benedikt Wefers, Wolfgang Wurst, Melanie Schneider, Ignasi Forne, Kiril Bidzhekov, Ronald Naumann, Sander W. van der Laan, Markus Brandhofer, Martin Dichgans","doi":"10.1016/j.immuni.2025.01.003","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.01.003","url":null,"abstract":"Common genetic variants in a conserved <em>cis</em>-regulatory element (CRE) at histone deacetylase (<em>HDAC</em>)<em>9</em> are a major risk factor for cardiovascular disease, including stroke and coronary artery disease. Given the consistency of this association and its proinflammatory properties, we examined the mechanisms whereby HDAC9 regulates vascular inflammation. HDAC9 bound and mediated deacetylation of NLRP3 in the NACHT and LRR domains leading to inflammasome activation and lytic cell death. Targeted deletion of the critical CRE in mice increased <em>Hdac9</em> expression in myeloid cells to exacerbate inflammasome-dependent chronic inflammation. In human carotid endarterectomy samples, increased <em>HDAC9</em> expression was associated with atheroprogression and clinical plaque instability. Incorporation of TMP195, a class IIa HDAC inhibitor, into lipoprotein-based nanoparticles to target HDAC9 at the site of myeloid-driven vascular inflammation stabilized atherosclerotic plaques, implying a lower risk of plaque rupture and cardiovascular events. Our findings link HDAC9 to atherogenic inflammation and provide a paradigm for anti-inflammatory therapeutics for atherosclerosis.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"45 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049950","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 : 2025-01-24DOI: 10.1016/j.immuni.2025.01.002
Federico F. De Ponti, Anna Bujko, Zhuangzhuang Liu, Paul J. Collins, Sara Schuermans, Christian Maueroder, Seraja Amstelveen, Tinne Thoné, Liesbet Martens, John G. McKendrick, Pieter A. Louwe, Ana Sànchez Cruz, Wouter Saelens, Kylie P. Matchett, Kathryn J. Waller, Christian Zwicker, Aimée Buglar-Lamb, Bavo Vanneste, Fleur Parmentier, Mushida Binte Abdul Latib, Charlotte L. Scott
Our understanding of the functional heterogeneity of resident versus recruited macrophages in the diseased liver is limited. A population of recruited lipid-associated macrophages (LAMs) has been reported to populate the diseased liver alongside resident Kupffer cells (KCs). However, the precise roles of these distinct macrophage subsets remain elusive. Here, using proteogenomics, we have identified LAMs in multiple models of liver injury. Moreover, we found that this phenotype is not specific to recruited macrophages, as a subset of resident KCs can also adopt a LAM-like phenotype in the mouse and human liver. By combining genetic mouse models targeting the distinct populations, we determined that both recruited LAMs and resident LAM-like KCs play crucial roles in tissue repair. Specifically, triggering receptor expressed on myeloid cells 2 (TREM2) expression on either resident or recruited macrophages is required for the efficient clearance of dying cells, enhancing repair and preventing exacerbated fibrosis.
{"title":"Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair","authors":"Federico F. De Ponti, Anna Bujko, Zhuangzhuang Liu, Paul J. Collins, Sara Schuermans, Christian Maueroder, Seraja Amstelveen, Tinne Thoné, Liesbet Martens, John G. McKendrick, Pieter A. Louwe, Ana Sànchez Cruz, Wouter Saelens, Kylie P. Matchett, Kathryn J. Waller, Christian Zwicker, Aimée Buglar-Lamb, Bavo Vanneste, Fleur Parmentier, Mushida Binte Abdul Latib, Charlotte L. Scott","doi":"10.1016/j.immuni.2025.01.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.01.002","url":null,"abstract":"Our understanding of the functional heterogeneity of resident versus recruited macrophages in the diseased liver is limited. A population of recruited lipid-associated macrophages (LAMs) has been reported to populate the diseased liver alongside resident Kupffer cells (KCs). However, the precise roles of these distinct macrophage subsets remain elusive. Here, using proteogenomics, we have identified LAMs in multiple models of liver injury. Moreover, we found that this phenotype is not specific to recruited macrophages, as a subset of resident KCs can also adopt a LAM-like phenotype in the mouse and human liver. By combining genetic mouse models targeting the distinct populations, we determined that both recruited LAMs and resident LAM-like KCs play crucial roles in tissue repair. Specifically, triggering receptor expressed on myeloid cells 2 (TREM2) expression on either resident or recruited macrophages is required for the efficient clearance of dying cells, enhancing repair and preventing exacerbated fibrosis.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"51 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026726","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 : 2025-01-22DOI: 10.1016/j.immuni.2024.12.012
Iñaki Robles-Vera, Aitor Jarit-Cabanillas, Paola Brandi, María Martínez-López, Sarai Martínez-Cano, Manuel Rodrigo-Tapias, Marcos Femenía-Muiña, Ana Redondo-Urzainqui, Vanesa Nuñez, Cristina González-Correa, Javier Moleón, Juan Duarte, Laura Conejero, Pablo Mata-Martínez, Carmen María Díez-Rivero, Marta Bergón-Gutiérrez, Iván Fernández-López, Manuel J. Gómez, Ana Quintas, Ana Dopazo, David Sancho
Impairment of the intestinal barrier allows the systemic translocation of commensal bacteria, inducing a proinflammatory state in the host. Here, we investigated innate immune responses following increased gut permeability upon administration of dextran sulfate sodium (DSS) in mice. We found that Enterococcus faecalis translocated to the bone marrow following DSS treatment and induced trained immunity (TI) hallmarks in bone-marrow-derived mouse macrophages and human monocytes. DSS treatment or heat-killed E. faecalis reprogrammed bone marrow progenitors (BMPs), resulting in enhanced inflammatory responses in vitro and in vivo and protection against subsequent pathogen infections. The C-type lectin receptor Mincle (Clec4e) was essential for E. faecalis-induced TI in BMPs. Clec4e−/− mice showed impaired TI upon E. faecalis administration and reduced pathology following DSS treatment. Thus, Mincle sensing of E. faecalis induces TI that may have long-term effects on pathologies associated with increased gut permeability.
{"title":"Microbiota translocation following intestinal barrier disruption promotes Mincle-mediated training of myeloid progenitors in the bone marrow","authors":"Iñaki Robles-Vera, Aitor Jarit-Cabanillas, Paola Brandi, María Martínez-López, Sarai Martínez-Cano, Manuel Rodrigo-Tapias, Marcos Femenía-Muiña, Ana Redondo-Urzainqui, Vanesa Nuñez, Cristina González-Correa, Javier Moleón, Juan Duarte, Laura Conejero, Pablo Mata-Martínez, Carmen María Díez-Rivero, Marta Bergón-Gutiérrez, Iván Fernández-López, Manuel J. Gómez, Ana Quintas, Ana Dopazo, David Sancho","doi":"10.1016/j.immuni.2024.12.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.12.012","url":null,"abstract":"Impairment of the intestinal barrier allows the systemic translocation of commensal bacteria, inducing a proinflammatory state in the host. Here, we investigated innate immune responses following increased gut permeability upon administration of dextran sulfate sodium (DSS) in mice. We found that <em>Enterococcus faecalis</em> translocated to the bone marrow following DSS treatment and induced trained immunity (TI) hallmarks in bone-marrow-derived mouse macrophages and human monocytes. DSS treatment or heat-killed <em>E. faecalis</em> reprogrammed bone marrow progenitors (BMPs), resulting in enhanced inflammatory responses <em>in vitro</em> and <em>in vivo</em> and protection against subsequent pathogen infections. The C-type lectin receptor Mincle (<em>Clec4e</em>) was essential for <em>E. faecalis</em>-induced TI in BMPs. <em>Clec4e</em><sup><em>−/−</em></sup> mice showed impaired TI upon <em>E. faecalis</em> administration and reduced pathology following DSS treatment. Thus, Mincle sensing of <em>E. faecalis</em> induces TI that may have long-term effects on pathologies associated with increased gut permeability.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"46 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991969","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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