ImmunityPub Date : 2024-12-04DOI: 10.1016/j.immuni.2024.11.024
Seiji Kaji, Stefan A. Berghoff, Lena Spieth, Lennart Schlaphoff, Andrew O. Sasmita, Simona Vitale, Luca Büschgens, Shreeya Kedia, Martin Zirngibl, Taisiia Nazarenko, Alkmini Damkou, Leon Hosang, Constanze Depp, Frits Kamp, Patricia Scholz, David Ewers, Martin Giera, Till Ischebeck, Wolfgang Wurst, Benedikt Wefers, Mikael Simons
{"title":"Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis","authors":"Seiji Kaji, Stefan A. Berghoff, Lena Spieth, Lennart Schlaphoff, Andrew O. Sasmita, Simona Vitale, Luca Büschgens, Shreeya Kedia, Martin Zirngibl, Taisiia Nazarenko, Alkmini Damkou, Leon Hosang, Constanze Depp, Frits Kamp, Patricia Scholz, David Ewers, Martin Giera, Till Ischebeck, Wolfgang Wurst, Benedikt Wefers, Mikael Simons","doi":"10.1016/j.immuni.2024.11.024","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.024","url":null,"abstract":"(Immunity <em>57</em>, 2651–2668.e1–e12; November 12, 2024)","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"47 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776512","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}
ImmunityPub Date : 2024-12-03DOI: 10.1016/j.immuni.2024.11.009
Nouran S. Abdelfattah, Tomasz Kula, Stephen J. Elledge
{"title":"T-Switch: A specificity-based engineering platform for developing safe and effective T cell therapeutics","authors":"Nouran S. Abdelfattah, Tomasz Kula, Stephen J. Elledge","doi":"10.1016/j.immuni.2024.11.009","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.009","url":null,"abstract":"Many promising targets for adoptive T cell therapy (ACT) are self-antigens, but self-reactive T cells are generally eliminated during thymic selection or diverted to regulatory phenotypes. To bypass T cell tolerance and obtain potent and safe T cell therapeutics, we developed T-Switch, an <em>in vitro</em> T cell receptor (TCR) engineering platform for the creation, modification, and comprehensive profiling of TCRs that can target self-antigens. T-Switch first expands T cells that recognize a “foreign” peptide closely related to a self-antigen. The fine specificity of the TCR is then modified by directed evolution of the peptide binding region to switch its specificity to the self-antigen of interest. We applied T-Switch to engineer synthetic TCRs reactive to a tumor-associated self-antigen, validated the safety and efficacy of this approach, and detected no off-target recognition as measured against the human proteome. Thus, T-Switch represents a resource for the creation of collections of highly sensitive synthetic TCRs for T cell-based immunotherapies.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"80 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759923","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}
ImmunityPub Date : 2024-11-28DOI: 10.1016/j.immuni.2024.11.006
Caterina E. Faliti, Maria Mesina, Jinyong Choi, Simon Bélanger, Monique A. Marshall, Christopher M. Tipton, Sakeenah Hicks, Prashanti Chappa, Maria A. Cardenas, Mohamed Abdel-Hakeem, Theresa C. Thinnes, Christopher Cottrell, Christopher D. Scharer, William R. Schief, David Nemazee, Matthew C. Woodruff, John M. Lindner, Ignacio Sanz, Shane Crotty
{"title":"Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis","authors":"Caterina E. Faliti, Maria Mesina, Jinyong Choi, Simon Bélanger, Monique A. Marshall, Christopher M. Tipton, Sakeenah Hicks, Prashanti Chappa, Maria A. Cardenas, Mohamed Abdel-Hakeem, Theresa C. Thinnes, Christopher Cottrell, Christopher D. Scharer, William R. Schief, David Nemazee, Matthew C. Woodruff, John M. Lindner, Ignacio Sanz, Shane Crotty","doi":"10.1016/j.immuni.2024.11.006","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.006","url":null,"abstract":"During antigen-driven responses, B cells can differentiate at extra-follicular (EF) sites or initiate germinal centers (GCs) in processes that involve interactions with T cells. Here, we examined the roles of interleukin (IL)-2 secreted by T helper (Th) cells during cognate interactions with activated B cells. IL-2 boosted the expansion of EF plasma cells and the secretion of low-mutated immunoglobulin G (IgG). Conversely, genetically disrupting IL-2 expression by CD4<sup>+</sup> T cells, or IL-2 receptor (CD25) expression by B cells, promoted B cell entry into the GC and high-affinity antibody secretion. Mechanistically, IL-2 induced early mTOR activity, expression of the transcriptional regulator IRF4, and metabolic changes in B cells required to form Blimp-1-expressing plasma cells. Thus, T cell help via IL-2 regulates an mTOR-AKT-Blimp-1 axis in activated B cells, providing insight into the mechanisms that determine EF versus GC fates and positioning IL-2 as an early switch controlling plasma cell versus GC B cell commitment.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"8 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735576","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}
ImmunityPub Date : 2024-11-28DOI: 10.1016/j.immuni.2024.11.002
Milica Moskovljevic, Filippo Dragoni, Nathan L. Board, Fengting Wu, Jun Lai, Hao Zhang, James R. White, Rebecca Hoh, Kenneth Lynn, Pablo Tebas, Karam Mounzer, Steven G. Deeks, Luis J. Montaner, Janet D. Siliciano, Robert F. Siliciano, Francesco R. Simonetti
{"title":"Cognate antigen engagement induces HIV-1 expression in latently infected CD4+ T cells from people on long-term antiretroviral therapy","authors":"Milica Moskovljevic, Filippo Dragoni, Nathan L. Board, Fengting Wu, Jun Lai, Hao Zhang, James R. White, Rebecca Hoh, Kenneth Lynn, Pablo Tebas, Karam Mounzer, Steven G. Deeks, Luis J. Montaner, Janet D. Siliciano, Robert F. Siliciano, Francesco R. Simonetti","doi":"10.1016/j.immuni.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.002","url":null,"abstract":"Despite antiretroviral therapy (ART), HIV-1 persists in latently infected CD4<sup>+</sup> T cells, preventing a cure. Antigens drive the proliferation of infected cells, precluding latent reservoir decay. However, the relationship between antigen recognition and HIV-1 gene expression is poorly understood because most studies of latency reversal use agents that induce non-specific global T cell activation. Here, we isolated rare CD4<sup>+</sup> T cells responding to cytomegalovirus (CMV) or HIV-1 Gag antigens from people living with HIV-1 on long-term ART and assessed T cell activation and HIV-1 RNA expression upon coculture with autologous dendritic cells (DCs) presenting cognate antigens. Presentation of cognate antigens <em>ex vivo</em> induced broad T cell activation (median 42-fold increase in CD154<sup>+</sup>CD69<sup>+</sup> cells) and significantly increased HIV-1 transcription (median 4-fold), mostly through the induction of rare cells with higher viral expression. Thus, despite low proviral inducibility, antigen recognition can promote HIV-1 expression, potentially contributing to spontaneous reservoir activity and viral rebound upon ART interruption.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"25 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142735796","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}
ImmunityPub Date : 2024-11-27DOI: 10.1016/j.immuni.2024.11.004
Lucy MacDonald, Aziza Elmesmari, Domenico Somma, Jack Frew, Clara Di Mario, Roopa Madhu, Audrey Paoletti, Theodoros Simakou, Olympia M. Hardy, Barbara Tolusso, Denise Campobasso, Simone Perniola, Marco Gessi, Maria Rita Gigante, Luca Petricca, Dario Bruno, Lavinia Agra Coletto, Roberta Benvenuto, John D. Isaacs, Andrew Filby, Mariola Kurowska-Stolarska
{"title":"Synovial tissue myeloid dendritic cell subsets exhibit distinct tissue-niche localization and function in health and rheumatoid arthritis","authors":"Lucy MacDonald, Aziza Elmesmari, Domenico Somma, Jack Frew, Clara Di Mario, Roopa Madhu, Audrey Paoletti, Theodoros Simakou, Olympia M. Hardy, Barbara Tolusso, Denise Campobasso, Simone Perniola, Marco Gessi, Maria Rita Gigante, Luca Petricca, Dario Bruno, Lavinia Agra Coletto, Roberta Benvenuto, John D. Isaacs, Andrew Filby, Mariola Kurowska-Stolarska","doi":"10.1016/j.immuni.2024.11.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.004","url":null,"abstract":"Current rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to reinstate tolerance in RA. Using single-cell and spatial transcriptomics of ST biopsies, as well as co-culture systems, we identified condition- and niche-specific DC clusters with distinct functions. Healthy tissue contained tolerogenic AXL<sup>+</sup> DC2s in the lining niche. In active RA, the hyperplasic lining niche was populated with inflammatory DC3s that activated CCL5-positive effector memory T cells, promoting synovitis. Lymphoid niches that emerged in the sublining layer were enriched with CCR7<sup>+</sup> DC2s, which interacted with naive T cells, potentially driving the local expansion of new effector T cells. Remission saw the resolution of these pathogenic niches but lacked recovery of tolerogenic DC2s and exhibited activation of blood precursors of ST-DC3 clusters prior to flare-ups. Targeting pathogenic DC3s or restoring tolerogenic DC2s may help restore immune homeostasis in RA joints.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"163 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718786","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}
ImmunityPub Date : 2024-11-27DOI: 10.1016/j.immuni.2024.11.001
Xinkai Zou, Keyue Wang, Yujun Deng, Pengbo Guan, Qianlun Pu, Yuemeng Wang, Jun Mou, Yizhou Du, Xiaoxian Lou, Sijiao Wang, Na Jiang, Shengtao Zhou, Hui Wang, Dan Du, Xindong Liu, Hongbo Hu, Huiyuan Zhang
{"title":"Hypoxia-inducible factor 2α promotes pathogenic polarization of stem-like Th2 cells via modulation of phospholipid metabolism","authors":"Xinkai Zou, Keyue Wang, Yujun Deng, Pengbo Guan, Qianlun Pu, Yuemeng Wang, Jun Mou, Yizhou Du, Xiaoxian Lou, Sijiao Wang, Na Jiang, Shengtao Zhou, Hui Wang, Dan Du, Xindong Liu, Hongbo Hu, Huiyuan Zhang","doi":"10.1016/j.immuni.2024.11.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.001","url":null,"abstract":"T helper 2 (Th2) cells orchestrate immunity against parasite infection and promote tissue repair but promote pathology in asthma and tissue fibrosis. Here, we examined the mechanisms driving pathogenic differentiation of Th2 cells. Single-cell analyses of CD4<sup>+</sup> T cells from asthma and chronic rhinosinusitis patients revealed high expression of the hypoxia-inducible factor (HIF)2α in Th2 cells. In mice, HIF2α deficiency impaired Th2 differentiation and alleviated asthmatic inflammation. Single-cell and lineage tracing approaches delineated a differentiation trajectory from TCF1<sup>+</sup>Ly108<sup>+</sup> stem-like Th2 cells to the ST2<sup>+</sup>CD25<sup>+</sup> pathogenic progeny, depending on a HIF2α-GATA3 circuit that modulated phospholipid metabolism and T cell receptor (TCR)-phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) activation via transcriptional regulation of the inositol polyphosphate multikinase (IPMK). Overexpression of IPMK in HIF2α-deficient cells promoted Phosphatidylinositol (3,4,5)-trisphosphate (PIP<sub>3</sub>) synthesis and pathogenic Th2 cell differentiation, whereas pharmacological inhibition of HIF2α impaired pathogenic differentiation of Th2 cells and mitigated airway inflammation. Our findings provide insight into the contextual cues that promote Th2-mediated pathology and suggest HIF2α as a therapeutic target in asthma.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718789","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}
{"title":"Phase separation of chimeric antigen receptor promotes immunological synapse maturation and persistent cytotoxicity","authors":"Xinyi Xu, Haotian Chen, Zhengxu Ren, Xiaomin Xu, Wei Wu, Haochen Yang, JinJiao Wang, Yumeng Zhang, Qiuping Zhou, Hua Li, Shaoqing Zhang, Haopeng Wang, Chenqi Xu","doi":"10.1016/j.immuni.2024.11.005","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.005","url":null,"abstract":"Major challenges of chimeric antigen receptor (CAR)-T cell therapy include poor antigen sensitivity and cell persistence. Here, we report a solution to these issues by exploiting CAR phase separation. We found that incorporation of an engineered T cell receptor CD3ε motif, E<sub>B6I</sub>, into the conventional 28Z or BBZ CAR induced self-phase separation through cation-π interactions. E<sub>B6I</sub> CAR formed a mature immunological synapse with the CD2 corolla to transduce efficient antigen and costimulatory signaling, although its tonic signaling remained low. Functionally, E<sub>B6I</sub> CAR-T cells exhibited improved signaling and cytotoxicity against low-antigen tumor cells and persistent tumor-killing function. In multiple primary and relapsed murine tumor models, E<sub>B6I</sub> CAR-T cells exerted better antitumor functions than conventional CAR-T cells against blood and solid cancers. This study thus unveils a CAR engineering strategy to improve CAR-T cell immunity by leveraging molecular condensation and signaling integration.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"13 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718785","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}
ImmunityPub Date : 2024-11-26DOI: 10.1016/j.immuni.2024.10.014
Masato Ogishi, Koji Kitaoka, Kim L. Good-Jacobson, Darawan Rinchai, Baihao Zhang, Jun Wang, Vincent Gies, Geetha Rao, Tina Nguyen, Danielle T. Avery, Taushif Khan, Megan E. Smithmyer, Joseph Mackie, Rui Yang, Andrés Augusto Arias, Takaki Asano, Khoren Ponsin, Matthieu Chaldebas, Peng Zhang, Jessica N. Peel, Stuart G. Tangye
{"title":"Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling","authors":"Masato Ogishi, Koji Kitaoka, Kim L. Good-Jacobson, Darawan Rinchai, Baihao Zhang, Jun Wang, Vincent Gies, Geetha Rao, Tina Nguyen, Danielle T. Avery, Taushif Khan, Megan E. Smithmyer, Joseph Mackie, Rui Yang, Andrés Augusto Arias, Takaki Asano, Khoren Ponsin, Matthieu Chaldebas, Peng Zhang, Jessica N. Peel, Stuart G. Tangye","doi":"10.1016/j.immuni.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.014","url":null,"abstract":"T follicular helper (Tfh) cells abundantly express the immunoreceptor programmed cell death protein 1 (PD-1), and the impact of PD-1 deficiency on antibody (Ab)-mediated immunity in mice is associated with compromised Tfh cell functions. Here, we revisited the role of the PD-1-PD-L1 axis on Ab-mediated immunity. Individuals with inherited PD-1 or PD-L1 deficiency had fewer memory B cells and impaired Ab responses, similar to <em>Pdcd1</em><sup><em>−/−</em></sup> and <em>Cd274</em><sup><em>−/−</em></sup><em>Pdcd1lg2</em><sup><em>−/−</em></sup> mice. PD-1, PD-L1, or both could be detected on the surface of human naive B cells following <em>in vitro</em> activation. PD-1- or PD-L1-deficient B cells had reduced expression of the transcriptional regulator c-Myc and c-Myc-target genes <em>in vivo</em>, and PD-1 deficiency or neutralization of PD-1 or PD-L1 impeded c-Myc expression and Ab production in human B cells isolated <em>in vitro</em>. Furthermore, B cell-specific deletion of <em>Pdcd1</em> prevented the physiological accumulation of memory B cells in mice. Thus, PD-1 shapes optimal B cell memory and Ab-mediated immunity through B cell-intrinsic and B cell-extrinsic mechanisms, suggesting that B cell dysregulation contributes to infectious and autoimmune complications following anti-PD-1-PD-L1 immunotherapy.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"64 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713109","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}
ImmunityPub Date : 2024-11-21DOI: 10.1016/j.immuni.2024.10.015
Siyu Sun, Eunae You, Jungeui Hong, David Hoyos, Isabella S. Del Priore, Kaloyan M. Tsanov, Om Mattagajasingh, Andrea Di Gioacchino, Sajid A. Marhon, Jonathan Chacon-Barahona, Hao Li, Hua Jiang, Samira Hozeifi, Omar Rosas-Bringas, Katherine H. Xu, Yuhui Song, Evan R. Lang, Alexandra S. Rojas, Linda T. Nieman, Bidish K. Patel, Benjamin D. Greenbaum
{"title":"Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms","authors":"Siyu Sun, Eunae You, Jungeui Hong, David Hoyos, Isabella S. Del Priore, Kaloyan M. Tsanov, Om Mattagajasingh, Andrea Di Gioacchino, Sajid A. Marhon, Jonathan Chacon-Barahona, Hao Li, Hua Jiang, Samira Hozeifi, Omar Rosas-Bringas, Katherine H. Xu, Yuhui Song, Evan R. Lang, Alexandra S. Rojas, Linda T. Nieman, Bidish K. Patel, Benjamin D. Greenbaum","doi":"10.1016/j.immuni.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.015","url":null,"abstract":"To thrive, cancer cells must navigate acute inflammatory signaling accompanying oncogenic transformation, such as via overexpression of repeat elements. We examined the relationship between immunostimulatory repeat expression, tumor evolution, and the tumor-immune microenvironment. Integration of multimodal data from a cohort of pancreatic ductal adenocarcinoma (PDAC) patients revealed expression of specific Alu repeats predicted to form double-stranded RNAs (dsRNAs) and trigger retinoic-acid-inducible gene I (RIG-I)-like-receptor (RLR)-associated type-I interferon (IFN) signaling. Such Alu-derived dsRNAs also anti-correlated with pro-tumorigenic macrophage infiltration in late stage tumors. We defined two complementary pathways whereby PDAC may adapt to such anti-tumorigenic signaling. In mutant <em>TP53</em> tumors, ORF1p from long interspersed nuclear element (LINE)-1 preferentially binds Alus and decreases their expression, whereas adenosine deaminases acting on RNA 1 (ADAR1) editing primarily reduces dsRNA formation in wild-type <em>TP53</em> tumors. Depletion of either LINE-1 ORF1p or ADAR1 reduced tumor growth <em>in vitro</em>. The fact that tumors utilize multiple pathways to mitigate immunostimulatory repeats implies the stress from their expression is a fundamental phenomenon to which PDAC, and likely other tumors, adapt.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"192 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678284","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}
ImmunityPub Date : 2024-11-20DOI: 10.1016/j.immuni.2024.10.010
Yutao Wang, Yanbo Zhang, Kyungsub Kim, Jichang Han, Daniel Okin, Zhaozhao Jiang, Liang Yang, Arum Subramaniam, Terry K. Means, Frank O. Nestlé, Katherine A. Fitzgerald, Gwendalyn J. Randolph, Cammie F. Lesser, Jonathan C. Kagan, Diane Mathis, Christophe Benoist
{"title":"A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control","authors":"Yutao Wang, Yanbo Zhang, Kyungsub Kim, Jichang Han, Daniel Okin, Zhaozhao Jiang, Liang Yang, Arum Subramaniam, Terry K. Means, Frank O. Nestlé, Katherine A. Fitzgerald, Gwendalyn J. Randolph, Cammie F. Lesser, Jonathan C. Kagan, Diane Mathis, Christophe Benoist","doi":"10.1016/j.immuni.2024.10.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.010","url":null,"abstract":"Ligand-dependent transcription factors of the nuclear receptor (NR) family regulate diverse aspects of metazoan biology, enabling communications between distant organs via small lipophilic molecules. Here, we examined the impact of each of 35 NRs on differentiation and homeostatic maintenance of all major immunological cell types <em>in vivo</em> through a “Rainbow-CRISPR” screen. Receptors for retinoic acid exerted the most frequent cell-specific roles. NR requirements varied for resident macrophages of different tissues. Deletion of either <em>Rxra</em> or <em>Rarg</em> reduced frequencies of GATA6<sup>+</sup> large peritoneal macrophages (LPMs). Retinoid X receptor alpha (RXRα) functioned conventionally by orchestrating LPM differentiation through chromatin and transcriptional regulation, whereas retinoic acid receptor gamma (RARγ) controlled LPM survival by regulating pyroptosis via association with the inflammasome adaptor ASC. RARγ antagonists activated caspases, and RARγ agonists inhibited cell death induced by several inflammasome activators. Our findings provide a broad view of NR function in the immune system and reveal a noncanonical role for a retinoid receptor in modulating inflammasome pathways.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"53 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673170","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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