Pub Date : 2024-12-06DOI: 10.1016/j.immuni.2024.11.008
Mengyu Xia, Junmei Lu, Jiabin Lan, Teng Teng, Rani Shiao, Hongbin Sun, Zheyu Jin, Xueer Liu, Jie Wang, Hongyan Wu, Changchun Wang, Han Yi, Qingqing Qi, Jixi Li, Marc Schneeberger, Wei Shen, Boxun Lu, Lei Chen, Anoj Ilanges, Xinyu Zhou, Xiaofei Yu
Psychological stress and its sequelae pose a major challenge to public health. Immune activation is conventionally thought to aggravate stress-related mental diseases such as anxiety disorders and depression. Here, we sought to identify potentially beneficial consequences of immune activation in response to stress. We showed that stress led to increased interleukin (IL)-22 production in the intestine as a result of stress-induced gut leakage. IL-22 was both necessary and sufficient to attenuate stress-induced anxiety behaviors in mice. More specifically, IL-22 gained access to the septal area of the brain and directly suppressed neuron activation. Furthermore, human patients with clinical depression displayed reduced IL-22 levels, and exogenous IL-22 treatment ameliorated depressive-like behavior elicited by chronic stress in mice. Our study thus identifies a gut-brain axis in response to stress, whereby IL-22 reduces neuronal activation and concomitant anxiety behavior, suggesting that early immune activation can provide protection against psychological stress.
{"title":"Elevated IL-22 as a result of stress-induced gut leakage suppresses septal neuron activation to ameliorate anxiety-like behavior","authors":"Mengyu Xia, Junmei Lu, Jiabin Lan, Teng Teng, Rani Shiao, Hongbin Sun, Zheyu Jin, Xueer Liu, Jie Wang, Hongyan Wu, Changchun Wang, Han Yi, Qingqing Qi, Jixi Li, Marc Schneeberger, Wei Shen, Boxun Lu, Lei Chen, Anoj Ilanges, Xinyu Zhou, Xiaofei Yu","doi":"10.1016/j.immuni.2024.11.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.11.008","url":null,"abstract":"Psychological stress and its sequelae pose a major challenge to public health. Immune activation is conventionally thought to aggravate stress-related mental diseases such as anxiety disorders and depression. Here, we sought to identify potentially beneficial consequences of immune activation in response to stress. We showed that stress led to increased interleukin (IL)-22 production in the intestine as a result of stress-induced gut leakage. IL-22 was both necessary and sufficient to attenuate stress-induced anxiety behaviors in mice. More specifically, IL-22 gained access to the septal area of the brain and directly suppressed neuron activation. Furthermore, human patients with clinical depression displayed reduced IL-22 levels, and exogenous IL-22 treatment ameliorated depressive-like behavior elicited by chronic stress in mice. Our study thus identifies a gut-brain axis in response to stress, whereby IL-22 reduces neuronal activation and concomitant anxiety behavior, suggesting that early immune activation can provide protection against psychological stress.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"8 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142782541","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 : 2024-12-04DOI: 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
(Immunity 57, 2651–2668.e1–e12; November 12, 2024)
{"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}
Pub Date : 2024-12-03DOI: 10.1016/j.immuni.2024.11.009
Nouran S. Abdelfattah, Tomasz Kula, Stephen J. Elledge
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 in vitro 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.
{"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}
Pub 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
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+ 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.
在抗原驱动的应答过程中，B细胞可在滤泡外（EF）部位分化或启动生殖中心（GC），其过程涉及与T细胞的相互作用。在这里，我们研究了T辅助细胞（Th）在与活化B细胞发生同源相互作用时分泌的白细胞介素（IL）-2的作用。IL-2 促进了 EF 浆细胞的扩增和低变异免疫球蛋白 G (IgG) 的分泌。相反，从基因上破坏 CD4+ T 细胞的 IL-2 表达或 B 细胞的 IL-2 受体（CD25）表达，会促进 B 细胞进入 GC 并分泌高亲和力抗体。从机理上讲，IL-2诱导了早期mTOR活性、转录调节因子IRF4的表达，以及B细胞形成Blimp-1表达浆细胞所需的代谢变化。因此，T细胞通过IL-2帮助调节活化B细胞中的mTOR-AKT-Blimp-1轴，从而深入了解了决定EF与GC命运的机制，并将IL-2定位为控制浆细胞与GC B细胞承诺的早期开关。
{"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}
Pub 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
Despite antiretroviral therapy (ART), HIV-1 persists in latently infected CD4+ 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+ 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 ex vivo induced broad T cell activation (median 42-fold increase in CD154+CD69+ 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.
尽管采用了抗逆转录病毒疗法（ART），HIV-1 仍然存在于潜伏感染的 CD4+ T 细胞中，无法治愈。抗原促使受感染细胞增殖，从而阻止了潜伏库的衰减。然而，人们对抗原识别与 HIV-1 基因表达之间的关系知之甚少，因为大多数关于潜伏逆转的研究都使用了诱导非特异性全局 T 细胞活化的制剂。在这里，我们从长期接受抗逆转录病毒疗法的HIV-1感染者中分离出了对巨细胞病毒（CMV）或HIV-1 Gag抗原有反应的罕见CD4+T细胞，并评估了与呈现同源抗原的自体树突状细胞（DCs）共培养后的T细胞活化和HIV-1 RNA表达。体内递呈同源抗原可诱导广泛的T细胞活化（CD154+CD69+细胞中位数增加42倍），并显著增加HIV-1转录（中位数增加4倍），这主要是通过诱导病毒表达较高的稀有细胞实现的。因此，尽管病毒诱导性较低，但抗原识别可促进 HIV-1 的表达，从而有可能在抗逆转录病毒疗法中断后导致自发的储库活动和病毒反弹。
{"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}
Pub 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
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+ 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+ 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.
{"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}
Pub 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
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+ 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+Ly108+ stem-like Th2 cells to the ST2+CD25+ 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 (PIP3) 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.
T 辅助细胞 2（Th2）可协调免疫力，抵御寄生虫感染，促进组织修复，但也会导致哮喘和组织纤维化等病症。在这里，我们研究了 Th2 细胞致病分化的驱动机制。对哮喘和慢性鼻炎患者的 CD4+ T 细胞进行的单细胞分析表明，Th2 细胞中缺氧诱导因子（HIF）2α 的表达量很高。在小鼠中，HIF2α的缺乏会影响Th2分化，并减轻哮喘炎症。单细胞和细胞系追踪方法勾勒出了从TCF1+Ly108+干样Th2细胞到ST2+CD25+致病性祖细胞的分化轨迹、HIF2α-GATA3回路通过肌醇多磷酸激酶（IPMK）的转录调控调节磷脂代谢和T细胞受体（TCR）-磷脂酰肌醇3-激酶（PI3K）-蛋白激酶B（AKT）的激活。IPMK在HIF2α缺陷细胞中的过表达促进了磷脂酰肌醇（3,4,5）-三磷酸（PIP3）的合成和致病性Th2细胞的分化，而药物抑制HIF2α则会抑制Th2细胞的致病性分化并减轻气道炎症。我们的研究结果让人们深入了解了促进 Th2 细胞介导的病理学的背景线索，并建议将 HIF2α 作为哮喘的治疗靶点。
{"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}
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, EB6I, into the conventional 28Z or BBZ CAR induced self-phase separation through cation-π interactions. EB6I CAR formed a mature immunological synapse with the CD2 corolla to transduce efficient antigen and costimulatory signaling, although its tonic signaling remained low. Functionally, EB6I 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, EB6I 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.
嵌合抗原受体（CAR）-T 细胞疗法面临的主要挑战包括抗原敏感性差和细胞持久性。在此，我们报告了利用 CAR 相分离解决这些问题的方法。我们发现，在传统的28Z或BBZ CAR中加入工程化T细胞受体CD3ε基团EB6I，可通过阳离子-π相互作用诱导自相位分离。EB6I CAR与CD2花冠形成了成熟的免疫突触，可传递高效的抗原和成本刺激信号，但其强直性信号仍然较低。在功能上，EB6I CAR-T 细胞对低抗原肿瘤细胞的信号转导和细胞毒性得到了改善，并具有持续的肿瘤杀伤功能。在多个原发性和复发性小鼠肿瘤模型中，EB6I CAR-T细胞比传统的CAR-T细胞对血癌和实体瘤具有更好的抗肿瘤功能。因此，这项研究揭示了一种 CAR 工程策略，即利用分子凝集和信号整合来提高 CAR-T 细胞的免疫力。
{"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}
Pub 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
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 Pdcd1−/− and Cd274−/−Pdcd1lg2−/− mice. PD-1, PD-L1, or both could be detected on the surface of human naive B cells following in vitro activation. PD-1- or PD-L1-deficient B cells had reduced expression of the transcriptional regulator c-Myc and c-Myc-target genes in vivo, and PD-1 deficiency or neutralization of PD-1 or PD-L1 impeded c-Myc expression and Ab production in human B cells isolated in vitro. Furthermore, B cell-specific deletion of Pdcd1 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.
T滤泡辅助细胞（Tfh）大量表达免疫受体程序性细胞死亡蛋白1（PD-1），PD-1缺乏症对小鼠抗体（Ab）介导免疫的影响与Tfh细胞功能受损有关。在这里，我们重新审视了 PD-1-PD-L1 轴在抗体介导的免疫中的作用。与 Pdcd1-/- 和 Cd274-/-Pdcd1lg2-/- 小鼠相似，遗传性 PD-1 或 PD-L1 缺乏的个体记忆 B 细胞较少，Ab 反应受损。体外激活后，可在人类幼稚 B 细胞表面检测到 PD-1、PD-L1 或两者。PD-1或PD-L1缺陷的B细胞体内转录调节因子c-Myc和c-Myc靶基因的表达减少，PD-1缺陷或PD-1或PD-L1中和阻碍了体外分离的人B细胞中c-Myc的表达和Ab的产生。此外，B 细胞特异性缺失 Pdcd1 可阻止小鼠记忆 B 细胞的生理性积累。因此，PD-1通过B细胞内在和B细胞外在机制塑造了最佳的B细胞记忆和Ab介导的免疫力，这表明B细胞失调是抗PD-1-PD-L1免疫疗法后感染和自身免疫并发症的诱因。
{"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}
Pub 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
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 TP53 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 TP53 tumors. Depletion of either LINE-1 ORF1p or ADAR1 reduced tumor growth in vitro. 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.
{"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}
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