Pub Date : 2024-11-12DOI: 10.1016/j.immuni.2024.10.007
Ziyi Li, Ankur Sharma
The mechanisms by which oncogenic mutations and anatomical locations work together to influence the immune environment within tumors are not well understood. In this issue of Immunity, Ross et al. show that H3.3K27M diffuse midline gliomas (DMGs) are enriched with disease-associated myeloid cells (DAMs). Myeloid-targeted strategies reprogram DAMs to a homeostatic state, reduce myeloid infiltration into tumors, and prolong survival.
{"title":"Navigating the mutation maze: An oncogenic driver’s guide to macrophage reprogramming","authors":"Ziyi Li, Ankur Sharma","doi":"10.1016/j.immuni.2024.10.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.007","url":null,"abstract":"The mechanisms by which oncogenic mutations and anatomical locations work together to influence the immune environment within tumors are not well understood. In this issue of <em>Immunity</em>, Ross et al. show that H3.3K27M diffuse midline gliomas (DMGs) are enriched with disease-associated myeloid cells (DAMs). Myeloid-targeted strategies reprogram DAMs to a homeostatic state, reduce myeloid infiltration into tumors, and prolong survival.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"63 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599881","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 : 2024-11-06DOI: 10.1016/j.immuni.2024.10.003
Julia Davis-Porada, Alex B. George, Nora Lam, Daniel P. Caron, Joshua I. Gray, Jenny Huang, Jennifer Hwu, Steven B. Wells, Rei Matsumoto, Masaru Kubota, YoonSeung Lee, Rory Morrison-Colvin, Isaac J. Jensen, Basak B. Ural, Namir Shaabani, Daniela Weiskopf, Alba Grifoni, Alessandro Sette, Peter A. Szabo, John R. Teijaro, Donna L. Farber
Memory T and B cells in tissues are essential for protective immunity. Here, we performed a comprehensive analysis of the tissue distribution, phenotype, durability, and transcriptional profile of COVID-19 mRNA vaccine-induced immune memory across blood, lymphoid organs, and lungs obtained from 63 vaccinated organ donors aged 23–86, some of whom experienced SARS-CoV-2 infection. Spike (S)-reactive memory T cells were detected in lymphoid organs and lungs and variably expressed tissue-resident markers based on infection history, and S-reactive B cells comprised class-switched memory cells resident in lymphoid organs. Compared with blood, S-reactive tissue memory T cells persisted for longer times post-vaccination and were more prevalent with age. S-reactive T cells displayed site-specific subset compositions and functions: regulatory cell profiles were enriched in tissues, while effector and cytolytic profiles were more abundant in circulation. Our findings reveal functional compartmentalization of vaccine-induced T cell memory where surveilling effectors and in situ regulatory responses confer protection with minimal tissue damage.
组织中的记忆性 T 细胞和 B 细胞对保护性免疫至关重要。在这里，我们对 COVID-19 mRNA 疫苗诱导的免疫记忆在血液、淋巴器官和肺部的组织分布、表型、持久性和转录谱进行了全面分析，研究对象是 63 名年龄在 23-86 岁之间的器官捐献者，其中一些人曾感染过 SARS-CoV-2。在淋巴器官和肺部检测到尖峰（S）反应记忆T细胞，并根据感染史不同表达不同的组织驻留标记，S反应B细胞包括驻留在淋巴器官的类调换记忆细胞。与血液相比，S反应性组织记忆T细胞在接种疫苗后持续存在的时间更长，而且随着年龄的增长更为普遍。S 反应性 T 细胞显示出特定部位的亚群组成和功能：调节细胞特征在组织中更为丰富，而效应细胞和细胞溶解特征在循环中更为丰富。我们的研究结果揭示了疫苗诱导的 T 细胞记忆的功能分区，在这些分区中，监测效应细胞和原位调节反应可提供保护，同时将组织损伤降到最低。
{"title":"Maintenance and functional regulation of immune memory to COVID-19 vaccines in tissues","authors":"Julia Davis-Porada, Alex B. George, Nora Lam, Daniel P. Caron, Joshua I. Gray, Jenny Huang, Jennifer Hwu, Steven B. Wells, Rei Matsumoto, Masaru Kubota, YoonSeung Lee, Rory Morrison-Colvin, Isaac J. Jensen, Basak B. Ural, Namir Shaabani, Daniela Weiskopf, Alba Grifoni, Alessandro Sette, Peter A. Szabo, John R. Teijaro, Donna L. Farber","doi":"10.1016/j.immuni.2024.10.003","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.003","url":null,"abstract":"Memory T and B cells in tissues are essential for protective immunity. Here, we performed a comprehensive analysis of the tissue distribution, phenotype, durability, and transcriptional profile of COVID-19 mRNA vaccine-induced immune memory across blood, lymphoid organs, and lungs obtained from 63 vaccinated organ donors aged 23–86, some of whom experienced SARS-CoV-2 infection. Spike (S)-reactive memory T cells were detected in lymphoid organs and lungs and variably expressed tissue-resident markers based on infection history, and S-reactive B cells comprised class-switched memory cells resident in lymphoid organs. Compared with blood, S-reactive tissue memory T cells persisted for longer times post-vaccination and were more prevalent with age. S-reactive T cells displayed site-specific subset compositions and functions: regulatory cell profiles were enriched in tissues, while effector and cytolytic profiles were more abundant in circulation. Our findings reveal functional compartmentalization of vaccine-induced T cell memory where surveilling effectors and <em>in situ</em> regulatory responses confer protection with minimal tissue damage.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"90 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142588819","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 : 2024-11-01DOI: 10.1016/j.immuni.2024.10.001
Megi Rexhepaj, Daniel Asarnow, Lisa Perruzza, Young-Jun Park, Barbara Guarino, Mathew Mccallum, Katja Culap, Christian Saliba, Giada Leoni, Alessio Balmelli, Courtney N. Yoshiyama, Miles S. Dickinson, Joel Quispe, Jack T. Brown, M. Alejandra Tortorici, Kaitlin R. Sprouse, Ashley L. Taylor, Davide Corti, Tyler N. Starr, Fabio Benigni, David Veesler
Porcine delta-coronavirus (PDCoV) spillovers were recently detected in febrile children, underscoring the recurrent zoonoses of divergent CoVs. To date, no vaccines or specific therapeutics are approved for use in humans against PDCoV. To prepare for possible future PDCoV epidemics, we isolated PDCoV spike (S)-directed monoclonal antibodies (mAbs) from humanized mice and found that two, designated PD33 and PD41, broadly neutralized a panel of PDCoV variants. Cryoelectron microscopy (cryo-EM) structures of PD33 and PD41 in complex with the S receptor-binding domain (RBD) and ectodomain trimer revealed the epitopes recognized by these mAbs, rationalizing their broad inhibitory activity. We show that both mAbs competitively interfere with host aminopeptidase N binding to neutralize PDCoV and used deep-mutational scanning epitope mapping to associate RBD antigenic sites with mAb-mediated neutralization potency. Our results indicate a PD33-PD41 mAb cocktail may heighten the barrier to escape. PD33 and PD41 are candidates for clinical advancement against future PDCoV outbreaks.
最近在发热儿童中发现了猪三角冠状病毒（PDCoV）的外溢，这突显了不同的 CoVs 在人畜间的反复传播。迄今为止，还没有针对 PDCoV 的疫苗或特定疗法获准用于人类。为了应对未来可能出现的 PDCoV 流行病，我们从人源化小鼠体内分离出了 PDCoV 穗状病毒（S）定向单克隆抗体 (mAbs)，并发现 PD33 和 PD41 这两种单克隆抗体能广泛中和一系列 PDCoV 变种。PD33 和 PD41 与 S 受体结合域（RBD）和外显子三聚体的冷冻电子显微镜（cryo-EM）结构揭示了这些 mAbs 识别的表位，从而使其广泛的抑制活性更加合理。我们发现这两种 mAb 都能竞争性地干扰宿主氨肽酶 N 的结合，从而中和 PDCoV，并利用深度突变扫描表位图谱将 RBD 抗原位点与 mAb 介导的中和效力联系起来。我们的研究结果表明，PD33-PD41 mAb 鸡尾酒可增强逃逸障碍。PD33 和 PD41 是应对未来 PDCoV 爆发的候选临床药物。
{"title":"Isolation and escape mapping of broadly neutralizing antibodies against emerging delta-coronaviruses","authors":"Megi Rexhepaj, Daniel Asarnow, Lisa Perruzza, Young-Jun Park, Barbara Guarino, Mathew Mccallum, Katja Culap, Christian Saliba, Giada Leoni, Alessio Balmelli, Courtney N. Yoshiyama, Miles S. Dickinson, Joel Quispe, Jack T. Brown, M. Alejandra Tortorici, Kaitlin R. Sprouse, Ashley L. Taylor, Davide Corti, Tyler N. Starr, Fabio Benigni, David Veesler","doi":"10.1016/j.immuni.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.001","url":null,"abstract":"Porcine delta-coronavirus (PDCoV) spillovers were recently detected in febrile children, underscoring the recurrent zoonoses of divergent CoVs. To date, no vaccines or specific therapeutics are approved for use in humans against PDCoV. To prepare for possible future PDCoV epidemics, we isolated PDCoV spike (S)-directed monoclonal antibodies (mAbs) from humanized mice and found that two, designated PD33 and PD41, broadly neutralized a panel of PDCoV variants. Cryoelectron microscopy (cryo-EM) structures of PD33 and PD41 in complex with the S receptor-binding domain (RBD) and ectodomain trimer revealed the epitopes recognized by these mAbs, rationalizing their broad inhibitory activity. We show that both mAbs competitively interfere with host aminopeptidase N binding to neutralize PDCoV and used deep-mutational scanning epitope mapping to associate RBD antigenic sites with mAb-mediated neutralization potency. Our results indicate a PD33-PD41 mAb cocktail may heighten the barrier to escape. PD33 and PD41 are candidates for clinical advancement against future PDCoV outbreaks.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"79 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562148","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 : 2024-10-29DOI: 10.1016/j.immuni.2024.10.004
Yu Wang, Shaocun Zhang, Na Kang, Lihui Dong, Haochen Ni, Sichen Liu, Siankang Chong, Zhenglin Ji, Zhengpeng Wan, Xiangjun Chen, Fei Wang, Yun Lu, Baidong Hou, Pei Tong, Hai Qi, Meng Michelle Xu, Wanli Liu
Antigen-specific antibodies are generated by antibody-secreting cells (ASCs). How RNA post-transcriptional modification affects antibody homeostasis remains unclear. Here, we found that mRNA polyadenylations and N6-methyladenosine (m6A) modifications maintain IgG1 antibody production in ASCs. IgG heavy-chain transcripts (Ighg) possessed a long 3′ UTR with m6A sites, targeted by the m6A reader YTHDF1. B cell-specific deficiency of YTHDF1 impaired IgG production upon antigen immunization through reducing Ighg1 mRNA abundance in IgG1+ ASCs. Disrupting either the m6A modification of a nuclear-localized splicing intermediate Ighg1 or the nuclear localization of YTHDF1 reduced Ighg1 transcript stability. Single-cell RNA sequencing identified an ASC subset with excessive YTHDF1 expression in systemic lupus erythematosus patients, which was decreased upon therapy with immunosuppressive drugs. In a lupus mouse model, inhibiting YTHDF1-m6A interactions alleviated symptoms. Thus, we highlight a mechanism in ASCs to sustain the homeostasis of IgG antibody transcripts by integrating Ighg1 mRNA polyadenylation and m6A modification.
{"title":"Progressive polyadenylation and m6A modification of Ighg1 mRNA maintain IgG1 antibody homeostasis in antibody-secreting cells","authors":"Yu Wang, Shaocun Zhang, Na Kang, Lihui Dong, Haochen Ni, Sichen Liu, Siankang Chong, Zhenglin Ji, Zhengpeng Wan, Xiangjun Chen, Fei Wang, Yun Lu, Baidong Hou, Pei Tong, Hai Qi, Meng Michelle Xu, Wanli Liu","doi":"10.1016/j.immuni.2024.10.004","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.10.004","url":null,"abstract":"Antigen-specific antibodies are generated by antibody-secreting cells (ASCs). How RNA post-transcriptional modification affects antibody homeostasis remains unclear. Here, we found that mRNA polyadenylations and N6-methyladenosine (m6A) modifications maintain IgG1 antibody production in ASCs. IgG heavy-chain transcripts (<em>Ighg</em>) possessed a long 3′ UTR with m6A sites, targeted by the m6A reader YTHDF1. B cell-specific deficiency of YTHDF1 impaired IgG production upon antigen immunization through reducing <em>Ighg1</em> mRNA abundance in IgG1<sup>+</sup> ASCs. Disrupting either the m6A modification of a nuclear-localized splicing intermediate <em>Ighg1</em> or the nuclear localization of YTHDF1 reduced <em>Ighg1</em> transcript stability. Single-cell RNA sequencing identified an ASC subset with excessive YTHDF1 expression in systemic lupus erythematosus patients, which was decreased upon therapy with immunosuppressive drugs. In a lupus mouse model, inhibiting YTHDF1-m6A interactions alleviated symptoms. Thus, we highlight a mechanism in ASCs to sustain the homeostasis of IgG antibody transcripts by integrating <em>Ighg1</em> mRNA polyadenylation and m6A modification.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"237 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536596","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 : 2024-10-23DOI: 10.1016/j.immuni.2024.09.017
Davide Mangani, Ayshwarya Subramanian, Linglin Huang, Hanning Cheng, S. Harsha Krovi, Yufan Wu, Dandan Yang, Thais G. Moreira, Giulia Escobar, Alexandra Schnell, Karen O. Dixon, Rajesh K. Krishnan, Vasundhara Singh, Raymond A. Sobel, Howard L. Weiner, Vijay K. Kuchroo, Ana C. Anderson
T helper (Th) 17 cells encompass a spectrum of cell states, including cells that maintain homeostatic tissue functions and pro-inflammatory cells that can drive autoimmune tissue damage. Identifying regulators that determine Th17 cell states can identify ways to control tissue inflammation and restore homeostasis. Here, we found that interleukin (IL)-23, a cytokine critical for inducing pro-inflammatory Th17 cells, decreased transcription factor T cell factor 1 (TCF1) expression. Conditional deletion of TCF1 in mature T cells increased the pro-inflammatory potential of Th17 cells, even in the absence of IL-23 receptor signaling, and conferred pro-inflammatory potential to homeostatic Th17 cells. Conversely, sustained TCF1 expression decreased pro-inflammatory Th17 potential. Mechanistically, TCF1 bound to RORγt, thereby interfering with its pro-inflammatory functions, and orchestrated a regulatory network that determined Th17 cell state. Our findings identify TCF1 as a major determinant of Th17 cell state and provide important insight for the development of therapies for Th17-driven inflammatory diseases.
{"title":"Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state","authors":"Davide Mangani, Ayshwarya Subramanian, Linglin Huang, Hanning Cheng, S. Harsha Krovi, Yufan Wu, Dandan Yang, Thais G. Moreira, Giulia Escobar, Alexandra Schnell, Karen O. Dixon, Rajesh K. Krishnan, Vasundhara Singh, Raymond A. Sobel, Howard L. Weiner, Vijay K. Kuchroo, Ana C. Anderson","doi":"10.1016/j.immuni.2024.09.017","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.017","url":null,"abstract":"T helper (Th) 17 cells encompass a spectrum of cell states, including cells that maintain homeostatic tissue functions and pro-inflammatory cells that can drive autoimmune tissue damage. Identifying regulators that determine Th17 cell states can identify ways to control tissue inflammation and restore homeostasis. Here, we found that interleukin (IL)-23, a cytokine critical for inducing pro-inflammatory Th17 cells, decreased transcription factor T cell factor 1 (TCF1) expression. Conditional deletion of TCF1 in mature T cells increased the pro-inflammatory potential of Th17 cells, even in the absence of IL-23 receptor signaling, and conferred pro-inflammatory potential to homeostatic Th17 cells. Conversely, sustained TCF1 expression decreased pro-inflammatory Th17 potential. Mechanistically, TCF1 bound to RORγt, thereby interfering with its pro-inflammatory functions, and orchestrated a regulatory network that determined Th17 cell state. Our findings identify TCF1 as a major determinant of Th17 cell state and provide important insight for the development of therapies for Th17-driven inflammatory diseases.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"91 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487310","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 : 2024-10-16DOI: 10.1016/j.immuni.2024.09.014
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
The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer’s disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.
{"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.2024.09.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.014","url":null,"abstract":"The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer’s disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (<em>APOE</em>) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"92 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439689","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 : 2024-10-14DOI: 10.1016/j.immuni.2024.09.015
Andreas Obers, Tobias Poch, Grace Rodrigues, Susan N. Christo, Luke C. Gandolfo, Raissa Fonseca, Ali Zaid, Joey En Yu Kuai, Hongjin Lai, Pirooz Zareie, Marina H. Yakou, Lachlan Dryburgh, Thomas N. Burn, James Dosser, Frank A. Buquicchio, Caleb A. Lareau, Calum Walsh, Louise Judd, Maria Rafailia Theodorou, Katharina Gutbrod, Laura K. Mackay
Tissue-resident memory T (TRM) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common TRM cell fate remains poorly understood. Here, we show that whereas skin TRM cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive TRM cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal TRM populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated TRM cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues.
组织驻留记忆 T（TRM）细胞是组织免疫不可或缺的一部分，它们持续存在于不同的解剖部位，在那里它们遵循共同的转录框架。人们对这些细胞如何整合不同的局部线索以采用共同的TRM细胞命运仍然知之甚少。在这里，我们发现皮肤TRM细胞严格需要转化生长因子β（TGF-β）才能在组织中驻留，而其他部位的TRM细胞则利用代谢产物视黄酸（RA）来驱动另一种分化途径，在肝脏中引导不依赖于TGF-β的组织驻留程序，并与TGF-β协同驱动小肠中的TRM细胞。我们发现，肠道 TRM 群体的长期维持需要 RA，部分原因是 RA 阻碍了它们的逆向迁移。此外，增强的 RA 信号调节了 TRM 细胞的表型和功能，这一现象反映在微生物多样性增加的小鼠身上。总之，我们的研究结果揭示了 RA 是宿主与环境相互作用的基本组成部分，它引导着组织中的免疫监视。
{"title":"Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency","authors":"Andreas Obers, Tobias Poch, Grace Rodrigues, Susan N. Christo, Luke C. Gandolfo, Raissa Fonseca, Ali Zaid, Joey En Yu Kuai, Hongjin Lai, Pirooz Zareie, Marina H. Yakou, Lachlan Dryburgh, Thomas N. Burn, James Dosser, Frank A. Buquicchio, Caleb A. Lareau, Calum Walsh, Louise Judd, Maria Rafailia Theodorou, Katharina Gutbrod, Laura K. Mackay","doi":"10.1016/j.immuni.2024.09.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.015","url":null,"abstract":"Tissue-resident memory T (T<sub>RM</sub>) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common T<sub>RM</sub> cell fate remains poorly understood. Here, we show that whereas skin T<sub>RM</sub> cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive T<sub>RM</sub> cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal T<sub>RM</sub> populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated T<sub>RM</sub> cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"84 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431863","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 : 2024-10-14DOI: 10.1016/j.immuni.2024.09.013
Jana L. Raynor, Nicholas Collins, Hao Shi, Cliff Guy, Jordy Saravia, Seon Ah Lim, Nicole M. Chapman, Peipei Zhou, Yan Wang, Yu Sun, Isabel Risch, Haoran Hu, Anil KC, Renqiang Sun, Sharad Shrestha, Hongling Huang, Jon P. Connelly, Shondra M. Pruett-Miller, Miguel Reina-Campos, Ananda W. Goldrath, Hongbo Chi
Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using in vivo CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8+ tissue-resident memory T (TRM) cell development. TRM cells depended on mitochondrial translation and respiration. Conversely, three nutrient-dependent lysosomal signaling nodes—Flcn, Ragulator, and Rag GTPases—inhibited intestinal TRM cell formation. Depleting these molecules or amino acids activated the transcription factor Tfeb, thereby linking nutrient stress to TRM programming. Further, Flcn deficiency promoted protective TRM cell responses in the small intestine. Mechanistically, the Flcn-Tfeb axis restrained retinoic acid-induced CCR9 expression for migration and transforming growth factor β (TGF-β)-mediated programming for lineage differentiation. Genetic interaction screening revealed that the mitochondrial protein Mrpl52 enabled early TRM cell formation, while Acss1 controlled TRM cell development under Flcn deficiency-associated lysosomal dysregulation. Thus, the interplay between nutrients, organelle signaling, and metabolic adaptation dictates tissue immunity.
{"title":"CRISPR screens unveil nutrient-dependent lysosomal and mitochondrial nodes impacting intestinal tissue-resident memory CD8+ T cell formation","authors":"Jana L. Raynor, Nicholas Collins, Hao Shi, Cliff Guy, Jordy Saravia, Seon Ah Lim, Nicole M. Chapman, Peipei Zhou, Yan Wang, Yu Sun, Isabel Risch, Haoran Hu, Anil KC, Renqiang Sun, Sharad Shrestha, Hongling Huang, Jon P. Connelly, Shondra M. Pruett-Miller, Miguel Reina-Campos, Ananda W. Goldrath, Hongbo Chi","doi":"10.1016/j.immuni.2024.09.013","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.013","url":null,"abstract":"Nutrient availability and organelle biology direct tissue homeostasis and cell fate, but how these processes orchestrate tissue immunity remains poorly defined. Here, using <em>in vivo</em> CRISPR-Cas9 screens, we uncovered organelle signaling and metabolic processes shaping CD8<sup>+</sup> tissue-resident memory T (T<sub>RM</sub>) cell development. T<sub>RM</sub> cells depended on mitochondrial translation and respiration. Conversely, three nutrient-dependent lysosomal signaling nodes—Flcn, Ragulator, and Rag GTPases—inhibited intestinal T<sub>RM</sub> cell formation. Depleting these molecules or amino acids activated the transcription factor Tfeb, thereby linking nutrient stress to T<sub>RM</sub> programming. Further, Flcn deficiency promoted protective T<sub>RM</sub> cell responses in the small intestine. Mechanistically, the Flcn-Tfeb axis restrained retinoic acid-induced CCR9 expression for migration and transforming growth factor β (TGF-β)-mediated programming for lineage differentiation. Genetic interaction screening revealed that the mitochondrial protein Mrpl52 enabled early T<sub>RM</sub> cell formation, while Acss1 controlled T<sub>RM</sub> cell development under Flcn deficiency-associated lysosomal dysregulation. Thus, the interplay between nutrients, organelle signaling, and metabolic adaptation dictates tissue immunity.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"1 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431864","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 : 2024-10-12DOI: 10.1016/j.immuni.2024.09.016
Nouf Aljobaily, Denise Allard, Bryant Perkins, Arielle Raugh, Tessa Galland, Yi Jing, W. Zac Stephens, Matthew L. Bettini, J. Scott Hale, Maria Bettini
Self-reactive T cells experience chronic antigen exposure but do not exhibit signs of exhaustion. Here, we investigated the mechanisms for sustained, functioning autoimmune CD4+ T cells despite chronic stimulation. Examination of T cell priming showed that CD4+ T cells activated in the absence of infectious signals retained TCF1 expression. At later time points and during blockade of new T cell recruitment, most islet-infiltrating autoimmune CD4+ T cells were TCF1+, although expression was reduced on a per T cell basis. The Tcf7 locus was epigenetically modified in circulating autoimmune CD4+ T cells, suggesting a pre-programmed de novo methylation of the locus in early stages of autoimmune CD4+ T cell differentiation. This mirrored the epigenetic profile of recently recruited CD4+CD62L+ T cells in the pancreas. Collectively, these data reveal a unique environment during autoimmune CD4+ T cell priming that allows T cells to fine-tune TCF1 expression and maintain long-term survival and function.
自我反应 T 细胞会长期暴露于抗原，但不会表现出衰竭的迹象。在这里，我们研究了自身免疫 CD4+ T 细胞在长期刺激下仍能持续发挥作用的机制。对 T 细胞引物的研究表明，在没有感染信号的情况下激活的 CD4+ T 细胞保留了 TCF1 的表达。在较晚的时间点和阻断新T细胞招募期间，大多数小岛浸润的自身免疫CD4+ T细胞都是TCF1+，尽管每个T细胞的表达量减少了。在循环的自身免疫 CD4+ T 细胞中，Tcf7 基因座发生了表观遗传学改变，这表明在自身免疫 CD4+ T 细胞分化的早期阶段，该基因座发生了预编程的从头甲基化。这反映了胰腺中最近招募的 CD4+CD62L+ T 细胞的表观遗传学特征。总之，这些数据揭示了自身免疫 CD4+ T 细胞初始化过程中的独特环境，它允许 T 细胞微调 TCF1 的表达并维持长期存活和功能。
{"title":"Autoimmune CD4+ T cells fine-tune TCF1 expression to maintain function and survive persistent antigen exposure during diabetes","authors":"Nouf Aljobaily, Denise Allard, Bryant Perkins, Arielle Raugh, Tessa Galland, Yi Jing, W. Zac Stephens, Matthew L. Bettini, J. Scott Hale, Maria Bettini","doi":"10.1016/j.immuni.2024.09.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.016","url":null,"abstract":"Self-reactive T cells experience chronic antigen exposure but do not exhibit signs of exhaustion. Here, we investigated the mechanisms for sustained, functioning autoimmune CD4<sup>+</sup> T cells despite chronic stimulation. Examination of T cell priming showed that CD4<sup>+</sup> T cells activated in the absence of infectious signals retained TCF1 expression. At later time points and during blockade of new T cell recruitment, most islet-infiltrating autoimmune CD4<sup>+</sup> T cells were TCF1<sup>+</sup>, although expression was reduced on a per T cell basis. The <em>Tcf7</em> locus was epigenetically modified in circulating autoimmune CD4<sup>+</sup> T cells, suggesting a pre-programmed <em>de novo</em> methylation of the locus in early stages of autoimmune CD4<sup>+</sup> T cell differentiation. This mirrored the epigenetic profile of recently recruited CD4<sup>+</sup>CD62L<sup>+</sup> T cells in the pancreas. Collectively, these data reveal a unique environment during autoimmune CD4<sup>+</sup> T cell priming that allows T cells to fine-tune TCF1 expression and maintain long-term survival and function.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"13 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142415602","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 : 2024-10-11DOI: 10.1016/j.immuni.2024.09.007
James L. Ross, Montserrat Puigdelloses-Vallcorba, Gonzalo Piñero, Nishant Soni, Wes Thomason, John DeSisto, Angelo Angione, Nadejda M. Tsankova, Maria G. Castro, Matthew Schniederjan, Nitin R. Wadhwani, G. Praveen Raju, Peter Morgenstern, Oren J. Becher, Adam L. Green, Alexander M. Tsankov, Dolores Hambardzumyan
Pediatric high-grade gliomas (pHGGs), including hemispheric pHGGs and diffuse midline gliomas (DMGs), harbor mutually exclusive tumor location-specific histone mutations. Using immunocompetent de novo mouse models of pHGGs, we demonstrated that myeloid cells were the predominant infiltrating non-neoplastic cell population. Single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunohistochemistry illustrated the presence of heterogeneous myeloid cell populations shaped by histone mutations and tumor location. Disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics were identified in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrated enrichment of DAMs. Genetic ablation of chemokines Ccl8 and Ccl12 resulted in a reduction of DAMs and an increase in lymphocyte infiltration, leading to increased survival of tumor-bearing mice. Pharmacologic inhibition of chemokine receptors CCR1 and CCR5 resulted in extended survival and decreased myeloid cell infiltration. This work establishes the tumor-promoting role of myeloid cells in DMG and the potential therapeutic opportunities for targeting them.
{"title":"Microglia and monocyte-derived macrophages drive progression of pediatric high-grade gliomas and are transcriptionally shaped by histone mutations","authors":"James L. Ross, Montserrat Puigdelloses-Vallcorba, Gonzalo Piñero, Nishant Soni, Wes Thomason, John DeSisto, Angelo Angione, Nadejda M. Tsankova, Maria G. Castro, Matthew Schniederjan, Nitin R. Wadhwani, G. Praveen Raju, Peter Morgenstern, Oren J. Becher, Adam L. Green, Alexander M. Tsankov, Dolores Hambardzumyan","doi":"10.1016/j.immuni.2024.09.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2024.09.007","url":null,"abstract":"Pediatric high-grade gliomas (pHGGs), including hemispheric pHGGs and diffuse midline gliomas (DMGs), harbor mutually exclusive tumor location-specific histone mutations. Using immunocompetent <em>de novo</em> mouse models of pHGGs, we demonstrated that myeloid cells were the predominant infiltrating non-neoplastic cell population. Single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunohistochemistry illustrated the presence of heterogeneous myeloid cell populations shaped by histone mutations and tumor location. Disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics were identified in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrated enrichment of DAMs. Genetic ablation of chemokines <em>Ccl8</em> and <em>Ccl12</em> resulted in a reduction of DAMs and an increase in lymphocyte infiltration, leading to increased survival of tumor-bearing mice. Pharmacologic inhibition of chemokine receptors CCR1 and CCR5 resulted in extended survival and decreased myeloid cell infiltration. This work establishes the tumor-promoting role of myeloid cells in DMG and the potential therapeutic opportunities for targeting them.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"20 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405141","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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