Pub Date : 2024-05-03DOI: 10.1126/sciimmunol.adk0865
Rui Li, Yanting Lei, Ayman Rezk, Diego A. Espinoza, Jing Wang, Huiru Feng, Bo Zhang, Isabella P. Barcelos, Hang Zhang, Jing Yu, Xinrui Huo, Fangyi Zhu, Changxin Yang, Hao Tang, Amy C. Goldstein, Brenda L. Banwell, Hakon Hakonarson, Hongwei Xu, Michael Mingueneau, Bo Sun, Hulun Li, Amit Bar-Or
Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF–expressing) and anti-inflammatory (IL-10–expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a “fourth signal” that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.
B 细胞细胞因子分泌失调是包括多发性硬化症（MS）在内的免疫介导疾病的发病机制之一；然而，人们对其潜在机制却知之甚少。在这项研究中，我们调查了促炎性（表达 GM-CSF）和抗炎性（表达 IL-10）B 细胞分泌细胞因子的调节方式。与抗炎 B 细胞相比，促炎性人类 B 细胞需要增加氧化磷酸化（OXPHOS）。OXPHOS 通过调节三磷酸腺苷（ATP）信号传导相互调节促炎和抗炎 B 细胞的细胞因子。部分抑制 OXPHOS 或 ATP 信号转导（包括抑制 BTK）可导致抗炎性 B 细胞细胞因子的转变，逆转多发性硬化症患者体内 B 细胞细胞因子的失衡，并改善髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑炎小鼠模型的神经炎症。我们的研究确定了促炎细胞因子和抗炎细胞因子如何在 B 细胞中进行代谢调节，并确定 ATP 及其代谢产物是影响 B 细胞反应的 "第四信号"，是恢复自身免疫性疾病中 B 细胞细胞因子平衡的潜在靶点。
{"title":"Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis","authors":"Rui Li, Yanting Lei, Ayman Rezk, Diego A. Espinoza, Jing Wang, Huiru Feng, Bo Zhang, Isabella P. Barcelos, Hang Zhang, Jing Yu, Xinrui Huo, Fangyi Zhu, Changxin Yang, Hao Tang, Amy C. Goldstein, Brenda L. Banwell, Hakon Hakonarson, Hongwei Xu, Michael Mingueneau, Bo Sun, Hulun Li, Amit Bar-Or","doi":"10.1126/sciimmunol.adk0865","DOIUrl":"10.1126/sciimmunol.adk0865","url":null,"abstract":"<div >Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF–expressing) and anti-inflammatory (IL-10–expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a “fourth signal” that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140821701","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 : 2024-04-26DOI: 10.1126/sciimmunol.adh2334
Tianxiang Zhang, Weiwei Yu, Xiaoxiao Cheng, Jacky Yeung, Viviana Ahumada, Paul C. Norris, Mackenzie J. Pearson, Xuan Yang, Willemijn van Deursen, Christina Halcovich, Ala Nassar, Mathew D. Vesely, Yu Zhang, Jianping Zhang, Lan Ji, Dallas B. Flies, Linda Liu, Solomon Langermann, William J. LaRochelle, Rachel Humphrey, Dejian Zhao, Qiuyu Zhang, Jindong Zhang, Runxia Gu, Kurt A. Schalper, Miguel F. Sanmamed, Lieping Chen
T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell–recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells from infiltration, resulting in resistance to anti–PD-1 immunotherapy. PLA2G10 can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated T cell mobility. Ablation of PLA2G10’s enzymatic activity enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapies. Our study implicates a role for PLA2G10 in T cell exclusion from tumors and suggests a potential target for cancer immunotherapy.
在自发诱导免疫和治疗性免疫疗法过程中，即使存在功能性 T 细胞募集趋化因子系统，人类癌症组织中也经常缺乏 T 细胞，这表明存在影响浸润的 T 细胞排斥机制。利用全基因组体外筛选平台，我们确定了磷脂酶 A2 组 10（PLA2G10）蛋白在 T 细胞排斥中的作用。PLA2G10 在人类癌症中广泛上调，与肿瘤组织中 T 细胞浸润不良有关。PLA2G10在免疫原性小鼠肿瘤中的过表达会排斥T细胞浸润，从而导致抗PD-1免疫疗法的抗药性。PLA2G10 可将磷脂水解成小的脂质代谢物，从而抑制趋化因子介导的 T 细胞移动。消减PLA2G10的酶活性可增强T细胞浸润，并使PLA2G10过表达的肿瘤对免疫疗法敏感。我们的研究揭示了 PLA2G10 在肿瘤排斥 T 细胞中的作用，并为癌症免疫疗法提供了一个潜在靶点。
{"title":"Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity","authors":"Tianxiang Zhang, Weiwei Yu, Xiaoxiao Cheng, Jacky Yeung, Viviana Ahumada, Paul C. Norris, Mackenzie J. Pearson, Xuan Yang, Willemijn van Deursen, Christina Halcovich, Ala Nassar, Mathew D. Vesely, Yu Zhang, Jianping Zhang, Lan Ji, Dallas B. Flies, Linda Liu, Solomon Langermann, William J. LaRochelle, Rachel Humphrey, Dejian Zhao, Qiuyu Zhang, Jindong Zhang, Runxia Gu, Kurt A. Schalper, Miguel F. Sanmamed, Lieping Chen","doi":"10.1126/sciimmunol.adh2334","DOIUrl":"10.1126/sciimmunol.adh2334","url":null,"abstract":"<div >T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell–recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells from infiltration, resulting in resistance to anti–PD-1 immunotherapy. PLA2G10 can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated T cell mobility. Ablation of PLA2G10’s enzymatic activity enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapies. Our study implicates a role for PLA2G10 in T cell exclusion from tumors and suggests a potential target for cancer immunotherapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140651270","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 : 2024-04-26DOI: 10.1126/sciimmunol.adh0085
Jikai Cui, Heng Xu, Jizhang Yu, Shuan Ran, Xi Zhang, Yuan Li, Zhang Chen, Yuqing Niu, Song Wang, Weicong Ye, Wenhao Chen, Jie Wu, Jiahong Xia
Thymic negative selection of the T cell receptor (TCR) repertoire is essential for establishing self-tolerance and acquired allograft tolerance following organ transplantation. However, it is unclear whether and how peripheral clonal deletion of alloreactive T cells induces transplantation tolerance. Here, we establish that programmed cell death protein 1 (PD-1) is a hallmark of alloreactive T cells and is associated with clonal expansion after alloantigen encounter. Moreover, we found that diphtheria toxin receptor (DTR)–mediated ablation of PD-1+ cells reshaped the TCR repertoire through peripheral clonal deletion of alloreactive T cells and promoted tolerance in mouse transplantation models. In addition, by using PD-1–specific depleting antibodies, we found that antibody-mediated depletion of PD-1+ cells prevented heart transplant rejection and the development of experimental autoimmune encephalomyelitis (EAE) in humanized PD-1 mice. Thus, these data suggest that PD-1 is an attractive target for peripheral clonal deletion and induction of immune tolerance.
胸腺负性选择 T 细胞受体（TCR）复合物对建立器官移植后的自身耐受性和获得性异体移植耐受性至关重要。然而，异体活性 T 细胞外周克隆性删除是否以及如何诱导移植耐受尚不清楚。在这里，我们发现程序性细胞死亡蛋白 1（PD-1）是异体活性 T 细胞的标志，与异体抗原相遇后的克隆扩增有关。此外，我们还发现，白喉毒素受体（DTR）介导的 PD-1+ 细胞消融可通过异体活性 T 细胞外周克隆性删除重塑 TCR 重排，并促进小鼠移植模型的耐受性。此外，通过使用 PD-1 特异性清除抗体，我们发现抗体介导的 PD-1+ 细胞清除可防止心脏移植排斥反应和人源化 PD-1 小鼠实验性自身免疫性脑脊髓炎（EAE）的发生。因此，这些数据表明，PD-1 是外周克隆清除和诱导免疫耐受的一个有吸引力的靶点。
{"title":"Targeted depletion of PD-1–expressing cells induces immune tolerance through peripheral clonal deletion","authors":"Jikai Cui, Heng Xu, Jizhang Yu, Shuan Ran, Xi Zhang, Yuan Li, Zhang Chen, Yuqing Niu, Song Wang, Weicong Ye, Wenhao Chen, Jie Wu, Jiahong Xia","doi":"10.1126/sciimmunol.adh0085","DOIUrl":"10.1126/sciimmunol.adh0085","url":null,"abstract":"<div >Thymic negative selection of the T cell receptor (TCR) repertoire is essential for establishing self-tolerance and acquired allograft tolerance following organ transplantation. However, it is unclear whether and how peripheral clonal deletion of alloreactive T cells induces transplantation tolerance. Here, we establish that programmed cell death protein 1 (PD-1) is a hallmark of alloreactive T cells and is associated with clonal expansion after alloantigen encounter. Moreover, we found that diphtheria toxin receptor (DTR)–mediated ablation of PD-1<sup>+</sup> cells reshaped the TCR repertoire through peripheral clonal deletion of alloreactive T cells and promoted tolerance in mouse transplantation models. In addition, by using PD-1–specific depleting antibodies, we found that antibody-mediated depletion of PD-1<sup>+</sup> cells prevented heart transplant rejection and the development of experimental autoimmune encephalomyelitis (EAE) in humanized PD-1 mice. Thus, these data suggest that PD-1 is an attractive target for peripheral clonal deletion and induction of immune tolerance.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140651275","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 : 2024-04-19DOI: 10.1126/sciimmunol.adg7549
Pablo Canales-Herrerias, Mathieu Uzzan, Akihiro Seki, Rafael S. Czepielewski, Bram Verstockt, Alexandra E. Livanos, Fiona Raso, Alexandra Dunn, Daniel Dai, Andrew Wang, Zainab Al-taie, Jerome Martin, Thomas Laurent, Huaibin M. Ko, Minami Tokuyama, Michael Tankelevich, Hadar Meringer, Francesca Cossarini, Divya Jha, Azra Krek, John D. Paulsen, Matthew D. Taylor, Mohammad Zuber Nakadar, Joshua Wong, Emma C. Erlich, Rachel L. Mintz, Emily J. Onufer, Beth A. Helmink, Keshav Sharma, Adam Rosenstein, Danielle Ganjian, Grace Chung, Travis Dawson, Julius Juarez, Vijay Yajnik, Andrea Cerutti, Jeremiah J. Faith, Mayte Suarez-Farinas, Carmen Argmann, Francesca Petralia, Gwendalyn J. Randolph, Alexandros D. Polydorides, Andrea Reboldi, Jean-Frederic Colombel, Saurabh Mehandru
Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4β7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (β7+) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4β7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of β7+IgG+ plasmablasts in circulation, as well as IgG+ plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4β7-targeted therapies, with major implications for this therapeutic paradigm in UC.
维多珠单抗（VDZ）是溃疡性结肠炎（UC）的一线治疗药物，其作用靶点是α4β7-粘膜血管地址素细胞粘附分子1（MAdCAM-1）轴。为了确定 VDZ 的作用机制，我们对五组不同的 UC 患者进行了研究。经 VDZ 治疗的患者肠道中幼稚 B 细胞和 T 细胞的减少以及循环中肠道归巢（β7+）浆细胞的减少表明，VDZ 针对的是肠道相关淋巴组织（GALT）。在野生型小鼠和光电转换型（KikGR）小鼠体内进行的抗α4β7阻断试验证实，由于细胞进入功能受损，肠道相关淋巴组织的大小和细胞数量都会减少。在接受过 VDZ 治疗的 UC 患者中，治疗应答者的肠道淋巴聚集体大小和滤泡组织减少，循环中的β7+IgG+浆细胞以及肠道中的 IgG+浆细胞和 FcγR 依赖性信号减少。GALT靶向代表了α4β7靶向疗法以前未被重视的作用机制，对UC的这种治疗模式具有重大意义。
{"title":"Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis","authors":"Pablo Canales-Herrerias, Mathieu Uzzan, Akihiro Seki, Rafael S. Czepielewski, Bram Verstockt, Alexandra E. Livanos, Fiona Raso, Alexandra Dunn, Daniel Dai, Andrew Wang, Zainab Al-taie, Jerome Martin, Thomas Laurent, Huaibin M. Ko, Minami Tokuyama, Michael Tankelevich, Hadar Meringer, Francesca Cossarini, Divya Jha, Azra Krek, John D. Paulsen, Matthew D. Taylor, Mohammad Zuber Nakadar, Joshua Wong, Emma C. Erlich, Rachel L. Mintz, Emily J. Onufer, Beth A. Helmink, Keshav Sharma, Adam Rosenstein, Danielle Ganjian, Grace Chung, Travis Dawson, Julius Juarez, Vijay Yajnik, Andrea Cerutti, Jeremiah J. Faith, Mayte Suarez-Farinas, Carmen Argmann, Francesca Petralia, Gwendalyn J. Randolph, Alexandros D. Polydorides, Andrea Reboldi, Jean-Frederic Colombel, Saurabh Mehandru","doi":"10.1126/sciimmunol.adg7549","DOIUrl":"10.1126/sciimmunol.adg7549","url":null,"abstract":"<div >Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4β7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (β7<sup>+</sup>) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4β7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of β7<sup>+</sup>IgG<sup>+</sup> plasmablasts in circulation, as well as IgG<sup>+</sup> plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4β7-targeted therapies, with major implications for this therapeutic paradigm in UC.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adg7549","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140621407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-19DOI: 10.1126/sciimmunol.adg1094
Simone A. Minnie, Olivia G. Waltner, Ping Zhang, Shuichiro Takahashi, Nicole S. Nemychenkov, Kathleen S. Ensbey, Christine R. Schmidt, Samuel R. W. Legg, Melissa Comstock, Julie R. Boiko, Ethan Nelson, Shruti S. Bhise, Alec B. Wilkens, Motoko Koyama, Madhav V. Dhodapkar, Marta Chesi, Stanley R. Riddell, Damian J. Green, Andrew Spencer, Scott N. Furlan, Geoffrey R. Hill
Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ+ TPHEX. We also observed IFN-γ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. An IFN-γ+ TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here, we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFN-γ+ TPHEX represent a potential target for immunotherapy of blood cancers.
慢性抗原刺激被认为会产生功能失调的 CD8 T 细胞。在这里，我们发现了骨髓肿瘤微环境中的一个 CD8 T 细胞亚群，尽管其表型（TPHEX）明显终末衰竭，但它表达颗粒酶、穿孔素和 IFN-γ。同时进行的基因表达和 DNA 可及性研究发现，编码这些功能蛋白的基因与 BATF 的表达和图案可及性相关。IFN-γ+ TPHEX能有效杀死骨髓瘤，其疗效与过渡性效应物相当，而疾病进展与IFN-γ+ TPHEX的数量缺陷相关。我们还在 CD19 靶向嵌合抗原受体 T 细胞中观察到 IFN-γ+ TPHEX，它能杀死 CD19+ 白血病细胞。在人类癌症（包括骨髓瘤和淋巴瘤）的 TEX 细胞中也重现了 IFN-γ+ TPHEX 基因特征。在这里，我们描述了血液恶性肿瘤中 TEX 亚群的特征，这种亚群自相矛盾地保持着功能，并有别于慢性病毒感染中发现的功能失调 TEX。因此，IFN-γ+ TPHEX 是血液癌症免疫疗法的潜在靶点。
{"title":"TIM-3+ CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies","authors":"Simone A. Minnie, Olivia G. Waltner, Ping Zhang, Shuichiro Takahashi, Nicole S. Nemychenkov, Kathleen S. Ensbey, Christine R. Schmidt, Samuel R. W. Legg, Melissa Comstock, Julie R. Boiko, Ethan Nelson, Shruti S. Bhise, Alec B. Wilkens, Motoko Koyama, Madhav V. Dhodapkar, Marta Chesi, Stanley R. Riddell, Damian J. Green, Andrew Spencer, Scott N. Furlan, Geoffrey R. Hill","doi":"10.1126/sciimmunol.adg1094","DOIUrl":"10.1126/sciimmunol.adg1094","url":null,"abstract":"<div >Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (T<sub>PHEX</sub>), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with <i>BATF</i> expression and motif accessibility. IFN-γ<sup>+</sup> T<sub>PHEX</sub> effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ<sup>+</sup> T<sub>PHEX</sub>. We also observed IFN-γ<sup>+</sup> T<sub>PHEX</sub> within CD19-targeted chimeric antigen receptor T cells, which killed CD19<sup>+</sup> leukemia cells. An IFN-γ<sup>+</sup> T<sub>PHEX</sub> gene signature was recapitulated in T<sub>EX</sub> cells from human cancers, including myeloma and lymphoma. Here, we characterize a T<sub>EX</sub> subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional T<sub>EX</sub> found in chronic viral infections. Thus, IFN-γ<sup>+</sup> T<sub>PHEX</sub> represent a potential target for immunotherapy of blood cancers.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140621405","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 : 2024-04-19DOI: 10.1126/sciimmunol.adg8817
Sicong Ma, Roger Sandhoff, Xiu Luo, Fuwei Shang, Qiaozhen Shi, Zhaolong Li, Jingxia Wu, Yanan Ming, Frank Schwarz, Alaa Madi, Nina Weisshaar, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Xin Yan, Kerstin Mohr, Nora ten Bosch, Zhe Li, Gernot Poschet, Hans-Reimer Rodewald, Nina Papavasiliou, Xi Wang, Pu Gao, Guoliang Cui
CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences Treg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1–dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits antitumor immunity.
{"title":"Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos","authors":"Sicong Ma, Roger Sandhoff, Xiu Luo, Fuwei Shang, Qiaozhen Shi, Zhaolong Li, Jingxia Wu, Yanan Ming, Frank Schwarz, Alaa Madi, Nina Weisshaar, Alessa Mieg, Marvin Hering, Ferdinand Zettl, Xin Yan, Kerstin Mohr, Nora ten Bosch, Zhe Li, Gernot Poschet, Hans-Reimer Rodewald, Nina Papavasiliou, Xi Wang, Pu Gao, Guoliang Cui","doi":"10.1126/sciimmunol.adg8817","DOIUrl":"10.1126/sciimmunol.adg8817","url":null,"abstract":"<div >CD4<sup>+</sup> regulatory T (T<sub>reg</sub>) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences T<sub>reg</sub> cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed T<sub>reg</sub> cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including <i>Pdcd1</i> (encoding PD-1), which promoted <i>Pdcd1</i> transcription and increased inducible T<sub>reg</sub> cell differentiation in vitro in a PD-1–dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for T<sub>reg</sub> cell differentiation and limits antitumor immunity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140621406","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 : 2024-04-12DOI: 10.1126/sciimmunol.add1967
Jia Zhao, Ilya Andreev, Hernandez Moura Silva
Resident tissue macrophages (RTMs) encompass a highly diverse set of cells abundantly present in every tissue and organ. RTMs are recognized as central players in innate immune responses, and more recently their importance beyond host defense has started to be highlighted. Despite sharing a universal name and several canonical markers, RTMs perform remarkably specialized activities tailored to sustain critical homeostatic functions of the organs they reside in. These cells can mediate neuronal communication, participate in metabolic pathways, and secrete growth factors. In this Review, we summarize how the division of labor among different RTM subsets helps support tissue homeostasis. We discuss how the local microenvironment influences the development of RTMs, the molecular processes they support, and how dysregulation of RTMs can lead to disease. Last, we highlight both the similarities and tissue-specific distinctions of key RTM subsets, aiming to coalesce recent classifications and perspectives into a unified view.
{"title":"Resident tissue macrophages: Key coordinators of tissue homeostasis beyond immunity","authors":"Jia Zhao, Ilya Andreev, Hernandez Moura Silva","doi":"10.1126/sciimmunol.add1967","DOIUrl":"10.1126/sciimmunol.add1967","url":null,"abstract":"<div >Resident tissue macrophages (RTMs) encompass a highly diverse set of cells abundantly present in every tissue and organ. RTMs are recognized as central players in innate immune responses, and more recently their importance beyond host defense has started to be highlighted. Despite sharing a universal name and several canonical markers, RTMs perform remarkably specialized activities tailored to sustain critical homeostatic functions of the organs they reside in. These cells can mediate neuronal communication, participate in metabolic pathways, and secrete growth factors. In this Review, we summarize how the division of labor among different RTM subsets helps support tissue homeostasis. We discuss how the local microenvironment influences the development of RTMs, the molecular processes they support, and how dysregulation of RTMs can lead to disease. Last, we highlight both the similarities and tissue-specific distinctions of key RTM subsets, aiming to coalesce recent classifications and perspectives into a unified view.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.add1967","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-12DOI: 10.1126/sciimmunol.adi1023
Ioanna Tiniakou, Pei-Feng Hsu, Lorena S. Lopez-Zepeda, Görkem Garipler, Eduardo Esteva, Nicholas M. Adams, Geunhyo Jang, Chetna Soni, Colleen M. Lau, Fan Liu, Alireza Khodadadi-Jamayran, Tori C. Rodrick, Drew Jones, Aristotelis Tsirigos, Uwe Ohler, Mark T. Bedford, Stephen D. Nimer, Vesa Kaartinen, Esteban O. Mazzoni, Boris Reizis
The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9–based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling. An orthogonal screen identified the transcriptional repressor Trim33 (TIF-1γ) as a regulator of DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, deletion of Trim33 caused rapid loss of DC progenitors, pDCs, and the cross-presenting cDC1 subset. Trim33-deficient Flt3+ progenitors up-regulated pro-inflammatory and macrophage-specific genes but failed to induce the DC differentiation program. Collectively, these data elucidate mechanisms that control Flt3L-driven differentiation of the entire DC lineage and identify Trim33 as its essential regulator.
树突状细胞（DC），包括抗原递呈型传统 DC（cDC）和产生细胞因子的浆细胞状 DC（pDC）的发育受生长因子 Flt3 配体（Flt3L）及其受体 Flt3 的控制。我们利用基于CRISPR-Cas9的筛选技术对Flt3L驱动的DC分化进行了基因剖析。全基因组筛选发现了直流分化的多个调节因子，包括TSC和GATOR1复合物的亚基，它们限制了祖细胞的生长，但通过抑制mTOR信号转导使直流分化得以实现。正交筛选发现转录抑制因子 Trim33（TIF-1γ）是直流分化的调节因子。体内条件性靶向研究发现，Trim33 在所有 DC 的发育过程中发挥着重要作用，但在单核细胞或粒细胞的发育过程中则不起作用。特别是，Trim33的缺失会导致DC祖细胞、pDCs和交叉呈递cDC1亚群的快速丧失。缺失 Trim33 的 Flt3+ 祖细胞能上调促炎症和巨噬细胞特异性基因，但不能诱导 DC 分化程序。总之，这些数据阐明了控制 Flt3L 驱动的整个 DC 系分化的机制，并确定 Trim33 是其重要的调节因子。
{"title":"Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation","authors":"Ioanna Tiniakou, Pei-Feng Hsu, Lorena S. Lopez-Zepeda, Görkem Garipler, Eduardo Esteva, Nicholas M. Adams, Geunhyo Jang, Chetna Soni, Colleen M. Lau, Fan Liu, Alireza Khodadadi-Jamayran, Tori C. Rodrick, Drew Jones, Aristotelis Tsirigos, Uwe Ohler, Mark T. Bedford, Stephen D. Nimer, Vesa Kaartinen, Esteban O. Mazzoni, Boris Reizis","doi":"10.1126/sciimmunol.adi1023","DOIUrl":"10.1126/sciimmunol.adi1023","url":null,"abstract":"<div >The development of dendritic cells (DCs), including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs), is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected Flt3L-driven DC differentiation using CRISPR-Cas9–based screening. Genome-wide screening identified multiple regulators of DC differentiation including subunits of TSC and GATOR1 complexes, which restricted progenitor growth but enabled DC differentiation by inhibiting mTOR signaling. An orthogonal screen identified the transcriptional repressor Trim33 (TIF-1γ) as a regulator of DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, deletion of Trim33 caused rapid loss of DC progenitors, pDCs, and the cross-presenting cDC1 subset. Trim33-deficient Flt3<sup>+</sup> progenitors up-regulated pro-inflammatory and macrophage-specific genes but failed to induce the DC differentiation program. Collectively, these data elucidate mechanisms that control Flt3L-driven differentiation of the entire DC lineage and identify Trim33 as its essential regulator.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550297","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 : 2024-04-05DOI: 10.1126/sciimmunol.adk0092
Lingling Zhang, Amparo Toboso-Navasa, Arief Gunawan, Abdouramane Camara, Rinako Nakagawa, Katja Finsterbusch, Probir Chakravarty, Rebecca Newman, Yang Zhang, Martin Eilers, Andreas Wack, Pavel Tolar, Kai-Michael Toellner, Dinis Pedro Calado
The transition from immunoglobulin M (IgM) to affinity-matured IgG antibodies is vital for effective humoral immunity. This is facilitated by germinal centers (GCs) through affinity maturation and preferential maintenance of IgG+ B cells over IgM+ B cells. However, it is not known whether the positive selection of the different Ig isotypes within GCs is dependent on specific transcriptional mechanisms. Here, we explored IgG1+ GC B cell transcription factor dependency using a CRISPR-Cas9 screen and conditional mouse genetics. We found that MIZ1 was specifically required for IgG1+ GC B cell survival during positive selection, whereas IgM+ GC B cells were largely independent. Mechanistically, MIZ1 induced TMBIM4, an ancestral anti-apoptotic protein that regulated inositol trisphosphate receptor (IP3R)–mediated calcium (Ca2+) mobilization downstream of B cell receptor (BCR) signaling in IgG1+ B cells. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction–induced IgG1+ GC cell death caused by excessive Ca2+ accumulation. This study uncovers a unique Ig isotype–specific dependency on a hitherto unidentified mechanism in GC-positive selection.
从免疫球蛋白 M (IgM) 到亲和成熟的 IgG 抗体的转变对于有效的体液免疫至关重要。生殖中心（GCs）通过亲和成熟和优先维持 IgG+ B 细胞而不是 IgM+ B 细胞促进了这一转变。然而，目前还不清楚生殖中心内不同 Ig 异型的正向选择是否依赖于特定的转录机制。在这里，我们使用 CRISPR-Cas9 筛选和条件小鼠遗传学方法探索了 IgG1+ GC B 细胞转录因子的依赖性。我们发现，在正向选择过程中，IgG1+ GC B 细胞的存活特别需要 MIZ1，而 IgM+ GC B 细胞在很大程度上是独立的。从机制上讲，MIZ1诱导了TMBIM4，TMBIM4是一种祖先的抗凋亡蛋白，可调节IgG1+ B细胞中B细胞受体（BCR）信号传导下游的肌醇三磷酸受体（IP3R）介导的钙（Ca2+）动员。MIZ1-TMBIM4 轴阻止了 Ca2+ 过度积累引起的线粒体功能障碍诱导的 IgG1+ GC 细胞死亡。这项研究揭示了一种独特的 Ig 同型特异性依赖性，即在 GC 阳性选择中存在一种迄今尚未发现的机制。
{"title":"Regulation of BCR-mediated Ca2+ mobilization by MIZ1-TMBIM4 safeguards IgG1+ GC B cell–positive selection","authors":"Lingling Zhang, Amparo Toboso-Navasa, Arief Gunawan, Abdouramane Camara, Rinako Nakagawa, Katja Finsterbusch, Probir Chakravarty, Rebecca Newman, Yang Zhang, Martin Eilers, Andreas Wack, Pavel Tolar, Kai-Michael Toellner, Dinis Pedro Calado","doi":"10.1126/sciimmunol.adk0092","DOIUrl":"10.1126/sciimmunol.adk0092","url":null,"abstract":"<div >The transition from immunoglobulin M (IgM) to affinity-matured IgG antibodies is vital for effective humoral immunity. This is facilitated by germinal centers (GCs) through affinity maturation and preferential maintenance of IgG<sup>+</sup> B cells over IgM<sup>+</sup> B cells. However, it is not known whether the positive selection of the different Ig isotypes within GCs is dependent on specific transcriptional mechanisms. Here, we explored IgG1<sup>+</sup> GC B cell transcription factor dependency using a CRISPR-Cas9 screen and conditional mouse genetics. We found that MIZ1 was specifically required for IgG1<sup>+</sup> GC B cell survival during positive selection, whereas IgM<sup>+</sup> GC B cells were largely independent. Mechanistically, MIZ1 induced TMBIM4, an ancestral anti-apoptotic protein that regulated inositol trisphosphate receptor (IP3R)–mediated calcium (Ca<sup>2+</sup>) mobilization downstream of B cell receptor (BCR) signaling in IgG1<sup>+</sup> B cells. The MIZ1-TMBIM4 axis prevented mitochondrial dysfunction–induced IgG1<sup>+</sup> GC cell death caused by excessive Ca<sup>2+</sup> accumulation. This study uncovers a unique Ig isotype–specific dependency on a hitherto unidentified mechanism in GC-positive selection.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140351783","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 : 2024-04-05DOI: 10.1126/sciimmunol.adj7168
Jonna Bister, Iva Filipovic, Dan Sun, Ylva Crona-Guterstam, Martin Cornillet, Andrea Ponzetta, Jakob Michaëlsson, Sebastian Gidlöf, Martin A. Ivarsson, Benedikt Strunz, Niklas K. Björkström
Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The human uterus undergoes constant regeneration and is exposed to distinct environmental factors. To assess uterine immune system variation, we performed a system-level analysis of endometrial and peripheral blood immune cells in monozygotic twins. Although most immune cell phenotypes in peripheral blood showed high genetic heritability, more variation was found in endometrial immune cells, indicating a stronger influence by environmental factors. Cytomegalovirus infection was identified to influence peripheral blood immune cell variability but had limited effect on endometrial immune cells. Instead, hormonal contraception shaped the local endometrial milieu and immune cell composition with minor influence on the systemic immune system. These results highlight that the magnitude of human immune system variation and factors influencing it can be tissue specific.
{"title":"Tissue-specific nonheritable influences drive endometrial immune system variation","authors":"Jonna Bister, Iva Filipovic, Dan Sun, Ylva Crona-Guterstam, Martin Cornillet, Andrea Ponzetta, Jakob Michaëlsson, Sebastian Gidlöf, Martin A. Ivarsson, Benedikt Strunz, Niklas K. Björkström","doi":"10.1126/sciimmunol.adj7168","DOIUrl":"10.1126/sciimmunol.adj7168","url":null,"abstract":"<div >Although human twin studies have revealed the combined contribution of heritable and environmental factors in shaping immune system variability in blood, the contribution of these factors to immune system variability in tissues remains unexplored. The human uterus undergoes constant regeneration and is exposed to distinct environmental factors. To assess uterine immune system variation, we performed a system-level analysis of endometrial and peripheral blood immune cells in monozygotic twins. Although most immune cell phenotypes in peripheral blood showed high genetic heritability, more variation was found in endometrial immune cells, indicating a stronger influence by environmental factors. Cytomegalovirus infection was identified to influence peripheral blood immune cell variability but had limited effect on endometrial immune cells. Instead, hormonal contraception shaped the local endometrial milieu and immune cell composition with minor influence on the systemic immune system. These results highlight that the magnitude of human immune system variation and factors influencing it can be tissue specific.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adj7168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140351778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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