Pub Date : 2024-05-16DOI: 10.1126/sciimmunol.adn0622
Xuesong Wang, Christopher A. Cottrell, Xiaozhen Hu, Rashmi Ray, Maria Bottermann, Paula Maldonado Villavicencio, Yu Yan, Zhenfei Xie, John E. Warner, Jordan Renae Ellis-Pugh, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Sergey Menis, Sebastian Rämisch, Saman Eskandarzadeh, Michael Kubitz, Ryan Tingle, Nicole Phelps, Bettina Groschel, Sunny Himansu, Andrea Carfi, Kathrin H. Kirsch, Stephanie R. Weldon, Usha Nair, William R. Schief, Facundo D. Batista
Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle–encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.
胚系靶向（GT）蛋白免疫原可诱导针对艾滋病病毒包膜（Env）CD4结合位点的VRC01级广谱中和抗体（bnAbs），已在临床试验中显示出良好的前景。在这里，我们在小鼠模型中对编码 eOD-GT8 60mer 的脂质纳米颗粒封装核苷 mRNA（mRNA-LNP）作为可溶性自组装纳米颗粒进行了临床前验证。在具有三个人源化 B 细胞系的模型中，这些细胞系都带有不同的 VRC01 前体 B 细胞受体（BCR），它们对 eOD-GT8 具有相似的亲和力。增殖推动了前体 B 细胞参与生殖中心；体细胞高突变的积累，包括在关键的 VRC01 类位置；以及三个前体系中两个系对增殖抗原和类原生抗原的亲和性成熟。我们在临床前验证了由 mRNA-LNP 编码的可溶性自组装纳米粒子的启动-启动方案，证明了多系细胞可沿着 bnAb 途径启动、启动和多样化。
{"title":"mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models","authors":"Xuesong Wang, Christopher A. Cottrell, Xiaozhen Hu, Rashmi Ray, Maria Bottermann, Paula Maldonado Villavicencio, Yu Yan, Zhenfei Xie, John E. Warner, Jordan Renae Ellis-Pugh, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Sergey Menis, Sebastian Rämisch, Saman Eskandarzadeh, Michael Kubitz, Ryan Tingle, Nicole Phelps, Bettina Groschel, Sunny Himansu, Andrea Carfi, Kathrin H. Kirsch, Stephanie R. Weldon, Usha Nair, William R. Schief, Facundo D. Batista","doi":"10.1126/sciimmunol.adn0622","DOIUrl":"10.1126/sciimmunol.adn0622","url":null,"abstract":"<div >Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle–encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adn0622","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953313","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 : 2024-05-10DOI: 10.1126/sciimmunol.adn0126
Alessandro Vacchini, Andrew Chancellor, Qinmei Yang, Rodrigo Colombo, Julian Spagnuolo, Giuliano Berloffa, Daniel Joss, Ove Øyås, Chiara Lecchi, Giulia De Simone, Aisha Beshirova, Vladimir Nosi, José Pedro Loureiro, Aurelia Morabito, Corinne De Gregorio, Michael Pfeffer, Verena Schaefer, Gennaro Prota, Alfred Zippelius, Jörg Stelling, Daniel Häussinger, Laura Brunelli, Peter Villalta, Marco Lepore, Enrico Davoli, Silvia Balbo, Lucia Mori, Gennaro De Libero
MR1T cells are a recently found class of T cells that recognize antigens presented by the major histocompatibility complex-I–related molecule MR1 in the absence of microbial infection. The nature of the self-antigens that stimulate MR1T cells remains unclear, hampering our understanding of their physiological role and therapeutic potential. By combining genetic, pharmacological, and biochemical approaches, we found that carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Stimulatory compounds formed by carbonyl adducts of nucleobases were detected within MR1 molecules produced by tumor cells, and their abundance and antigenicity were enhanced by drugs that induce carbonyl accumulation. Our data reveal carbonyl-nucleobase adducts as MR1T cell antigens. Recognizing cells under carbonyl stress allows MR1T cells to monitor cellular metabolic changes with physiological and therapeutic implications.
MR1T 细胞是最近发现的一类 T 细胞，它们能在没有微生物感染的情况下识别由主要组织相容性复合体 I 相关分子 MR1 呈递的抗原。刺激 MR1T 细胞的自身抗原的性质仍不清楚，这妨碍了我们对其生理作用和治疗潜力的了解。通过结合遗传学、药理学和生物化学方法，我们发现靶细胞中的羰基应激和核碱基代谢变化会促进 MR1T 细胞的活化。在肿瘤细胞产生的 MR1 分子中检测到了由核碱基的羰基加合物形成的刺激性化合物，诱导羰基积累的药物增强了这些化合物的丰度和抗原性。我们的数据揭示了羰基核碱基加合物是 MR1T 细胞抗原。通过识别羰基压力下的细胞，MR1T 细胞可以监测细胞代谢变化，从而产生生理和治疗意义。
{"title":"Nucleobase adducts bind MR1 and stimulate MR1-restricted T cells","authors":"Alessandro Vacchini, Andrew Chancellor, Qinmei Yang, Rodrigo Colombo, Julian Spagnuolo, Giuliano Berloffa, Daniel Joss, Ove Øyås, Chiara Lecchi, Giulia De Simone, Aisha Beshirova, Vladimir Nosi, José Pedro Loureiro, Aurelia Morabito, Corinne De Gregorio, Michael Pfeffer, Verena Schaefer, Gennaro Prota, Alfred Zippelius, Jörg Stelling, Daniel Häussinger, Laura Brunelli, Peter Villalta, Marco Lepore, Enrico Davoli, Silvia Balbo, Lucia Mori, Gennaro De Libero","doi":"10.1126/sciimmunol.adn0126","DOIUrl":"10.1126/sciimmunol.adn0126","url":null,"abstract":"<div >MR1T cells are a recently found class of T cells that recognize antigens presented by the major histocompatibility complex-I–related molecule MR1 in the absence of microbial infection. The nature of the self-antigens that stimulate MR1T cells remains unclear, hampering our understanding of their physiological role and therapeutic potential. By combining genetic, pharmacological, and biochemical approaches, we found that carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Stimulatory compounds formed by carbonyl adducts of nucleobases were detected within MR1 molecules produced by tumor cells, and their abundance and antigenicity were enhanced by drugs that induce carbonyl accumulation. Our data reveal carbonyl-nucleobase adducts as MR1T cell antigens. Recognizing cells under carbonyl stress allows MR1T cells to monitor cellular metabolic changes with physiological and therapeutic implications.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140905011","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 : 2024-05-10DOI: 10.1126/sciimmunol.adp9609
{"title":"Erratum for the Research Article “Transcriptomes and metabolism define mouse and human MAIT cell populations” by S. Chandra et al.","authors":"","doi":"10.1126/sciimmunol.adp9609","DOIUrl":"10.1126/sciimmunol.adp9609","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140905008","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 : 2024-05-10DOI: 10.1126/sciimmunol.adj9730
Chuan Qin, Min Zhang, Da-Peng Mou, Luo-Qi Zhou, Ming-Hao Dong, Liang Huang, Wen Wang, Song-Bai Cai, Yun-Fan You, Ke Shang, Jun Xiao, Di Wang, Chun-Rui Li, Yi Hao, Michael Heming, Long-Jun Wu, Gerd Meyer Zu Hörste, Chen Dong, Bi-Tao Bu, Dai-Shi Tian, Wei Wang
Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti–B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.
用于治疗神经系统自身免疫性疾病的嵌合抗原受体（CAR）T细胞免疫疗法前景广阔，但人们对CAR T细胞动力学和治疗后的免疫改变知之甚少。在这里，我们对接受抗B细胞成熟抗原（BCMA）CAR T细胞治疗的神经脊髓炎视谱系障碍（NMOSD）患者的配对脑脊液（CSF）和血液样本进行了单细胞多组学测序。增殖的细胞毒性类 CD8+ CAR T 细胞克隆被确定为自身免疫的主要效应因子。具有增强趋化特性的抗BCMA CAR T细胞能有效穿过血液-脑脊液屏障，消除脑脊液中的浆细胞和浆细胞，抑制神经炎症。输注产物中表达 CD44 的早期记忆表型可能与 CAR T 细胞在自身免疫中的持久性有关。此外，与来自血液恶性肿瘤的 CAR T 细胞相比，来自 NMOSD 患者的 CAR T 细胞显示出细胞毒性受抑制的独特特征。因此，我们提供了神经系统自身免疫疾病患者 CAR T 细胞功能的机理见解。
{"title":"Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity","authors":"Chuan Qin, Min Zhang, Da-Peng Mou, Luo-Qi Zhou, Ming-Hao Dong, Liang Huang, Wen Wang, Song-Bai Cai, Yun-Fan You, Ke Shang, Jun Xiao, Di Wang, Chun-Rui Li, Yi Hao, Michael Heming, Long-Jun Wu, Gerd Meyer Zu Hörste, Chen Dong, Bi-Tao Bu, Dai-Shi Tian, Wei Wang","doi":"10.1126/sciimmunol.adj9730","DOIUrl":"10.1126/sciimmunol.adj9730","url":null,"abstract":"<div >Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti–B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8<sup>+</sup> CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adj9730","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140905013","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 : 2024-05-10DOI: 10.1126/sciimmunol.adi4191
Michael P. Plebanek, Yue Xue, Y-Van Nguyen, Nicholas C. DeVito, Xueying Wang, Alisha Holtzhausen, Georgia M. Beasley, Balamayooran Theivanthiran, Brent A. Hanks
Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8+ T cell activation and suppressed melanoma progression. CD63+ mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63+ mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.
传统树突状细胞（DC）是抗肿瘤免疫的重要介质。因此，人们对癌症发展出的使DC在肿瘤微环境（TME）中丧失功能的机制知之甚少。在确定 CD63 为特异性表面标记物之后，我们证明成熟调节性 DC（mregDCs）会迁移到肿瘤引流淋巴结组织，并抑制 DC 抗原的反式交叉呈递，同时促进 T 辅助细胞 2 和调节性 T 细胞的分化。转录和代谢研究表明，mregDC的功能依赖于甲羟戊酸生物合成途径及其主转录因子SREBP2。我们发现，黑色素瘤衍生的乳酸能激活肿瘤 DC 中的 SREBP2，并通过同源性或耐受性成熟驱动传统 DC 转变为 mregDC。DC特异性基因沉默和药物抑制SREBP2可促进抗肿瘤CD8+ T细胞的活化并抑制黑色素瘤的进展。研究发现，CD63+ mregDCs 存在于几种临床前肿瘤模型的淋巴结和黑色素瘤患者的前哨淋巴结中。总之，这项研究表明，肿瘤乳酸刺激的SREBP2依赖性程序促进了CD63+ mregDC的发育和功能，同时也是克服TME免疫耐受的一个有希望的治疗靶点。
{"title":"A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression","authors":"Michael P. Plebanek, Yue Xue, Y-Van Nguyen, Nicholas C. DeVito, Xueying Wang, Alisha Holtzhausen, Georgia M. Beasley, Balamayooran Theivanthiran, Brent A. Hanks","doi":"10.1126/sciimmunol.adi4191","DOIUrl":"10.1126/sciimmunol.adi4191","url":null,"abstract":"<div >Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8<sup>+</sup> T cell activation and suppressed melanoma progression. CD63<sup>+</sup> mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63<sup>+</sup> mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140905055","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 : 2024-05-03DOI: 10.1126/sciimmunol.adq0015
Soyeon Kim, Jonathan S. Maltzman
Initial imprinting by type 1 interferons shapes memory B cell generation in chronic viral infection.
1 型干扰素的初始印记塑造了慢性病毒感染中记忆 B 细胞的生成。
{"title":"Everlasting first impressions in B cells","authors":"Soyeon Kim, Jonathan S. Maltzman","doi":"10.1126/sciimmunol.adq0015","DOIUrl":"10.1126/sciimmunol.adq0015","url":null,"abstract":"<div >Initial imprinting by type 1 interferons shapes memory B cell generation in chronic viral infection.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140842598","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 : 2024-05-03DOI: 10.1126/sciimmunol.adj7970
Michael Kilian, Mirco J. Friedrich, Kevin Hai-Ning Lu, David Vonhören, Selina Jansky, Julius Michel, Anna Keib, Saskia Stange, Nicolaj Hackert, Niklas Kehl, Markus Hahn, Antje Habel, Stefanie Jung, Kristine Jähne, Felix Sahm, Johannes Betge, Adelheid Cerwenka, Frank Westermann, Peter Dreger, Marc S. Raab, Nadja M. Meindl-Beinker, Matthias Ebert, Lukas Bunse, Carsten Müller-Tidow, Michael Schmitt, Michael Platten
Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory “checkpoint molecules,” such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell–intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells. Unlike other checkpoint molecules, B7H6 mediated NKp30-dependent recognition and subsequent cytolysis of activated T cells by NK cells. B7H6+ T cells were prevalent in the tissue and blood of several diseases, and their abundance in tumor tissue positively correlated with clinical response in a cohort of patients with immune checkpoint inhibitor–treated esophageal cancer. In humanized mouse models, NK cell surveillance via B7H6 limited the persistence and antitumor activity of CAR T cells, and its genetic deletion enhanced T cell proliferation and persistence. Together, we provide evidence of B7H6 protein expression by activated T cells and suggest the B7H6-NKp30 axis as a therapeutically actionable NK cell–dependent immune checkpoint that regulates human T cell function.
了解调节 T 细胞免疫的机制对于开发治疗与 T 细胞功能障碍相关疾病（包括自身免疫性疾病、慢性感染和癌症）的有效疗法至关重要。程序性细胞死亡蛋白-1等共同抑制性 "检查点分子 "可平衡T细胞内在信号的过度或长时间免疫激活。在这里，通过筛选T细胞上的自然杀伤（NK）细胞识别介质，我们发现免疫球蛋白超家族配体B7H6在活化的T细胞中高度表达，包括病人灌注的CD19靶向嵌合抗原受体（CAR）T细胞。与其他检查点分子不同，B7H6介导NKp30依赖性识别活化的T细胞，随后NK细胞对其进行细胞溶解。B7H6+T细胞普遍存在于多种疾病的组织和血液中，在一组接受免疫检查点抑制剂治疗的食管癌患者中，它们在肿瘤组织中的丰度与临床反应呈正相关。在人源化小鼠模型中，通过 B7H6 进行的 NK 细胞监控限制了 CAR T 细胞的持久性和抗肿瘤活性，而基因缺失则增强了 T 细胞的增殖和持久性。综上所述，我们提供了活化的T细胞表达B7H6蛋白的证据，并提出B7H6-NKp30轴是一种可用于治疗的依赖于NK细胞的免疫检查点，可调节人类T细胞的功能。
{"title":"The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance","authors":"Michael Kilian, Mirco J. Friedrich, Kevin Hai-Ning Lu, David Vonhören, Selina Jansky, Julius Michel, Anna Keib, Saskia Stange, Nicolaj Hackert, Niklas Kehl, Markus Hahn, Antje Habel, Stefanie Jung, Kristine Jähne, Felix Sahm, Johannes Betge, Adelheid Cerwenka, Frank Westermann, Peter Dreger, Marc S. Raab, Nadja M. Meindl-Beinker, Matthias Ebert, Lukas Bunse, Carsten Müller-Tidow, Michael Schmitt, Michael Platten","doi":"10.1126/sciimmunol.adj7970","DOIUrl":"10.1126/sciimmunol.adj7970","url":null,"abstract":"<div >Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory “checkpoint molecules,” such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell–intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells. Unlike other checkpoint molecules, B7H6 mediated NKp30-dependent recognition and subsequent cytolysis of activated T cells by NK cells. B7H6<sup>+</sup> T cells were prevalent in the tissue and blood of several diseases, and their abundance in tumor tissue positively correlated with clinical response in a cohort of patients with immune checkpoint inhibitor–treated esophageal cancer. In humanized mouse models, NK cell surveillance via B7H6 limited the persistence and antitumor activity of CAR T cells, and its genetic deletion enhanced T cell proliferation and persistence. Together, we provide evidence of B7H6 protein expression by activated T cells and suggest the B7H6-NKp30 axis as a therapeutically actionable NK cell–dependent immune checkpoint that regulates human T cell function.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140821582","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 : 2024-05-03DOI: 10.1126/sciimmunol.abq1558
William A. Miller-Little, Xing Chen, Vanessa Salazar, Caini Liu, Katarzyna Bulek, Julie Y. Zhou, Xiao Li, Olaf Stüve, Thaddeus Stappenbeck, George Dubyak, Junjie Zhao, Xiaoxia Li
Steroid resistance poses a major challenge for the management of autoimmune neuroinflammation. T helper 17 (TH17) cells are widely implicated in the pathology of steroid resistance; however, the underlying mechanisms are unknown. In this study, we identified that interleukin-1 receptor (IL-1R) blockade rendered experimental autoimmune encephalomyelitis (EAE) mice sensitive to dexamethasone (Dex) treatment. Interleukin-1β (IL-1β) induced a signal transducer and activator of transcription 5 (STAT5)–mediated steroid-resistant transcriptional program in TH17 cells, which promoted inflammatory cytokine production and suppressed Dex-induced anti-inflammatory genes. TH17-specific deletion of STAT5 ablated the IL-1β–induced steroid-resistant transcriptional program and rendered EAE mice sensitive to Dex treatment. IL-1β synergized with Dex to promote the STAT5-dependent expression of CD69 and the development of central nervous system (CNS)–resident CD69+ TH17 cells. Combined IL-1R blockade and Dex treatment ablated CNS-resident TH17 cells, reduced EAE severity, and prevented relapse. CD69+ tissue-resident TH17 cells were also detected in brain lesions of patients with multiple sclerosis. These findings (i) demonstrate that IL-1β–STAT5 signaling in TH17 cells mediates steroid resistance and (ii) identify a therapeutic strategy for reversing steroid resistance in TH17-mediated CNS autoimmunity.
{"title":"A TH17-intrinsic IL-1β–STAT5 axis drives steroid resistance in autoimmune neuroinflammation","authors":"William A. Miller-Little, Xing Chen, Vanessa Salazar, Caini Liu, Katarzyna Bulek, Julie Y. Zhou, Xiao Li, Olaf Stüve, Thaddeus Stappenbeck, George Dubyak, Junjie Zhao, Xiaoxia Li","doi":"10.1126/sciimmunol.abq1558","DOIUrl":"10.1126/sciimmunol.abq1558","url":null,"abstract":"<div >Steroid resistance poses a major challenge for the management of autoimmune neuroinflammation. T helper 17 (T<sub>H</sub>17) cells are widely implicated in the pathology of steroid resistance; however, the underlying mechanisms are unknown. In this study, we identified that interleukin-1 receptor (IL-1R) blockade rendered experimental autoimmune encephalomyelitis (EAE) mice sensitive to dexamethasone (Dex) treatment. Interleukin-1β (IL-1β) induced a signal transducer and activator of transcription 5 (STAT5)–mediated steroid-resistant transcriptional program in T<sub>H</sub>17 cells, which promoted inflammatory cytokine production and suppressed Dex-induced anti-inflammatory genes. T<sub>H</sub>17-specific deletion of STAT5 ablated the IL-1β–induced steroid-resistant transcriptional program and rendered EAE mice sensitive to Dex treatment. IL-1β synergized with Dex to promote the STAT5-dependent expression of CD69 and the development of central nervous system (CNS)–resident CD69<sup>+</sup> T<sub>H</sub>17 cells. Combined IL-1R blockade and Dex treatment ablated CNS-resident T<sub>H</sub>17 cells, reduced EAE severity, and prevented relapse. CD69<sup>+</sup> tissue-resident T<sub>H</sub>17 cells were also detected in brain lesions of patients with multiple sclerosis. These findings (i) demonstrate that IL-1β–STAT5 signaling in T<sub>H</sub>17 cells mediates steroid resistance and (ii) identify a therapeutic strategy for reversing steroid resistance in T<sub>H</sub>17-mediated CNS autoimmunity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140821689","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 : 2024-05-03DOI: 10.1126/sciimmunol.adq0013
Luciana Conde, Carolina Lucas
Antibody-based therapy depletes myeloid-biased hematopoietic stem cells (my-HSCs) to rejuvenate the immune system and improve immune responses in aged mice.
{"title":"The Benjamin Button effect on stem cells: Reversing the clock on aging immunity","authors":"Luciana Conde, Carolina Lucas","doi":"10.1126/sciimmunol.adq0013","DOIUrl":"10.1126/sciimmunol.adq0013","url":null,"abstract":"<div >Antibody-based therapy depletes myeloid-biased hematopoietic stem cells (my-HSCs) to rejuvenate the immune system and improve immune responses in aged mice.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 95","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140821607","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 : 2024-05-03DOI: 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":"9 95","pages":""},"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}
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