Pub Date : 2024-06-07DOI: 10.1126/sciimmunol.adq7284
Annabel Wallace, Kevin C. O’Connor
Whole-proteome autoantibody profiling reveals an immunological signature that predates the clinical onset of multiple sclerosis.
全蛋白组自身抗体分析揭示了多发性硬化症临床发病前的免疫特征。
{"title":"Hide-&-Go-PhiP-Seq: Finding an elusive predictive MS biomarker","authors":"Annabel Wallace, Kevin C. O’Connor","doi":"10.1126/sciimmunol.adq7284","DOIUrl":"10.1126/sciimmunol.adq7284","url":null,"abstract":"<div >Whole-proteome autoantibody profiling reveals an immunological signature that predates the clinical onset of multiple sclerosis.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288551","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 : 2024-06-07DOI: 10.1126/sciimmunol.adk8141
Taylor A. Heim, Austin C. Schultz, Ines Delclaux, Vanessa Cristaldi, Madeline J. Churchill, Katherine S. Ventre, Amanda W. Lund
Lymphatic transport shapes the homeostatic immune repertoire of lymph nodes (LNs). LN-resident memory T cells (TRMs) play an important role in site-specific immune memory, yet how LN TRMs form de novo after viral infection remains unclear. Here, we tracked the anatomical distribution of antiviral CD8+ T cells as they seeded skin and LN TRMs using a model of vaccinia virus–induced skin infection. LN TRMs localized to the draining LNs (dLNs) of infected skin, and their formation depended on the lymphatic egress of effector CD8+ T cells from the skin, already poised for residence. Effector CD8+ T cell transit through skin was required to populate LN TRMs in dLNs, a process reinforced by antigen encounter in skin. Furthermore, LN TRMs were protective against viral rechallenge in the absence of circulating memory T cells. These data suggest that a subset of tissue-infiltrating CD8+ T cells egress from tissues during viral clearance and establish a layer of regional protection in the dLN basin.
淋巴运输塑造了淋巴结（LN）的同种免疫复合物。淋巴结驻留的记忆 T 细胞（TRMs）在特定部位的免疫记忆中发挥着重要作用，但淋巴结 TRMs 在病毒感染后如何重新形成仍不清楚。在这里，我们利用疫苗病毒诱导的皮肤感染模型追踪了抗病毒 CD8+ T 细胞在皮肤和 LN TRMs 上播种时的解剖分布。LN TRMs定位于受感染皮肤的引流LNs（dLNs），它们的形成依赖于效应CD8+ T细胞从皮肤的淋巴排出，而效应CD8+ T细胞已经做好了定居的准备。效应CD8+ T细胞穿过皮肤是在dLNs中形成LN TRMs的必要条件，皮肤中的抗原相遇强化了这一过程。此外，在没有循环记忆 T 细胞的情况下，LN TRMs 对病毒再侵具有保护作用。这些数据表明，在病毒清除过程中，组织浸润的 CD8+ T 细胞亚群从组织中排出，并在 dLN 盆地建立了一层区域保护。
{"title":"Lymphatic vessel transit seeds cytotoxic resident memory T cells in skin draining lymph nodes","authors":"Taylor A. Heim, Austin C. Schultz, Ines Delclaux, Vanessa Cristaldi, Madeline J. Churchill, Katherine S. Ventre, Amanda W. Lund","doi":"10.1126/sciimmunol.adk8141","DOIUrl":"10.1126/sciimmunol.adk8141","url":null,"abstract":"<div >Lymphatic transport shapes the homeostatic immune repertoire of lymph nodes (LNs). LN-resident memory T cells (T<sub>RMs</sub>) play an important role in site-specific immune memory, yet how LN T<sub>RMs</sub> form de novo after viral infection remains unclear. Here, we tracked the anatomical distribution of antiviral CD8<sup>+</sup> T cells as they seeded skin and LN T<sub>RMs</sub> using a model of vaccinia virus–induced skin infection. LN T<sub>RMs</sub> localized to the draining LNs (dLNs) of infected skin, and their formation depended on the lymphatic egress of effector CD8<sup>+</sup> T cells from the skin, already poised for residence. Effector CD8<sup>+</sup> T cell transit through skin was required to populate LN T<sub>RMs</sub> in dLNs, a process reinforced by antigen encounter in skin. Furthermore, LN T<sub>RMs</sub> were protective against viral rechallenge in the absence of circulating memory T cells. These data suggest that a subset of tissue-infiltrating CD8<sup>+</sup> T cells egress from tissues during viral clearance and establish a layer of regional protection in the dLN basin.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288553","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 : 2024-05-31DOI: 10.1126/sciimmunol.adq3365
{"title":"Erratum for the Research Article “TGF-β specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf” by Y. Chang et al.","authors":"","doi":"10.1126/sciimmunol.adq3365","DOIUrl":"10.1126/sciimmunol.adq3365","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141966303","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 : 2024-05-31DOI: 10.1126/sciimmunol.adq3385
{"title":"Erratum for the Research Article “TGF-β specifies TFH versus TH17 cell fates in murine CD4+ T cells through c-Maf” by Y. Chang et al.","authors":"","doi":"10.1126/sciimmunol.adq3385","DOIUrl":"10.1126/sciimmunol.adq3385","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184465","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 : 2024-05-31DOI: 10.1126/sciimmunol.adj2654
Qiutong Huang, Wang H. J. Cao, Sophie Curio, Huiyang Yu, Renae Denman, Evelyn Chen, Jaring Schreuder, James Dight, M. Zeeshan Chaudhry, Nicolas Jacquelot, Verena C. Wimmer, Cyril Seillet, Tarik Möröy, Gabrielle T. Belz
Tissue-resident innate lymphoid cells (ILCs) play a vital role in the frontline defense of various tissues, including the lung. The development of type 2 ILCs (ILC2s) depends on transcription factors such as GATA3, RORα, GFI1, and Bcl11b; however, the factors regulating lung-resident ILC2s remain unclear. Through fate mapping analysis of the paralog transcription factors GFI1 and GFI1B, we show that GFI1 is consistently expressed during the transition from progenitor to mature ILC2s. In contrast, GFI1B expression is limited to specific subsets of bone marrow progenitors and lung-resident ILC progenitors. We found that GFI1B+ lung ILC progenitors represent a multi-lineage subset with tissue-resident characteristics and the potential to form lung-derived ILC subsets and liver-resident ILC1s. Loss of GFI1B in bone marrow progenitors led to the selective loss of lung-resident IL-18R+ ILCs and mature ILC2, subsequently preventing the emergence of effector ILCs that could protect the lung against inflammatory or tumor challenge.
{"title":"GFI1B specifies developmental potential of innate lymphoid cell progenitors in the lungs","authors":"Qiutong Huang, Wang H. J. Cao, Sophie Curio, Huiyang Yu, Renae Denman, Evelyn Chen, Jaring Schreuder, James Dight, M. Zeeshan Chaudhry, Nicolas Jacquelot, Verena C. Wimmer, Cyril Seillet, Tarik Möröy, Gabrielle T. Belz","doi":"10.1126/sciimmunol.adj2654","DOIUrl":"10.1126/sciimmunol.adj2654","url":null,"abstract":"<div >Tissue-resident innate lymphoid cells (ILCs) play a vital role in the frontline defense of various tissues, including the lung. The development of type 2 ILCs (ILC2s) depends on transcription factors such as GATA3, RORα, GFI1, and Bcl11b; however, the factors regulating lung-resident ILC2s remain unclear. Through fate mapping analysis of the paralog transcription factors GFI1 and GFI1B, we show that GFI1 is consistently expressed during the transition from progenitor to mature ILC2s. In contrast, GFI1B expression is limited to specific subsets of bone marrow progenitors and lung-resident ILC progenitors. We found that GFI1B<sup>+</sup> lung ILC progenitors represent a multi-lineage subset with tissue-resident characteristics and the potential to form lung-derived ILC subsets and liver-resident ILC1s. Loss of GFI1B in bone marrow progenitors led to the selective loss of lung-resident IL-18R<sup>+</sup> ILCs and mature ILC2, subsequently preventing the emergence of effector ILCs that could protect the lung against inflammatory or tumor challenge.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184449","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 : 2024-05-31DOI: 10.1126/sciimmunol.adl2171
Sai Xiao, Shoubao Ma, Baofa Sun, Wenchen Pu, Songqi Duan, Jingjing Han, Yaqun Hong, Jianying Zhang, Yong Peng, Chuan He, Ping Yi, Michael A. Caligiuri, Jianhua Yu
Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain–containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell–mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti–PD-L1 or anti–PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.
肿瘤通过各种机制逃避免疫系统的攻击。在这里，我们发现了由含YTH结构域的家族蛋白2（YTHDF2）介导的肿瘤免疫逃避的一个组成部分，YTHDF2是一种阅读蛋白，通常会破坏m6A修饰的mRNA的稳定性。在免疫功能正常的肿瘤模型中，肿瘤 YTHDF2 的缺失可抑制肿瘤生长并延长存活时间。从机理上讲，肿瘤 YTHDF2 缺乏会通过 CX3CL1 促进巨噬细胞的招募，并通过损害肿瘤糖酵解代谢增强 CD8+ T 细胞的线粒体呼吸。在有 IFN-γ 的情况下，肿瘤 YTHDF2 缺乏会促进炎性巨噬细胞极化和抗原递呈。此外，IFN-γ 还能诱导肿瘤 YTHDF2 自噬降解，从而使肿瘤细胞对 CD8+ T 细胞介导的细胞毒性敏感。最后，我们发现了一种能优先诱导YTHDF2降解的小分子化合物，这种化合物单独使用时具有强效抗肿瘤作用，但与抗PD-L1或抗PD-1抗体联合使用时效果更好。总之，YTHDF2似乎是一种协调免疫逃避的肿瘤内在调控因子，是增强癌症免疫疗法的一个有希望的靶点。
{"title":"The tumor-intrinsic role of the m6A reader YTHDF2 in regulating immune evasion","authors":"Sai Xiao, Shoubao Ma, Baofa Sun, Wenchen Pu, Songqi Duan, Jingjing Han, Yaqun Hong, Jianying Zhang, Yong Peng, Chuan He, Ping Yi, Michael A. Caligiuri, Jianhua Yu","doi":"10.1126/sciimmunol.adl2171","DOIUrl":"10.1126/sciimmunol.adl2171","url":null,"abstract":"<div >Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain–containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m<sup>6</sup>A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8<sup>+</sup> T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8<sup>+</sup> T cell–mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti–PD-L1 or anti–PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adl2171","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184478","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 : 2024-05-24DOI: 10.1126/sciimmunol.ade2094
Munetomo Takahashi, Tsz Y. So, Vitalina Chamberlain-Evans, Robert Hughes, Juan Carlos Yam-Puc, Katarzyna Kania, Michelle Ruhle, Tiffeney Mann, Martijn J. Schuijs, Paul Coupland, Dean Naisbitt, Timotheus Y. F. Halim, Paul A. Lyons, Pietro Lio, Rahul Roychoudhuri, Klaus Okkenhaug, David J. Adams, Ken G. C. Smith, Duncan I. Jodrell, Michael A. Chapman, James E. D. Thaventhiran
Immunotherapy advances have been hindered by difficulties in tracking the behaviors of lymphocytes after antigen signaling. Here, we assessed the behavior of T cells active within tumors through the development of the antigen receptor signaling reporter (AgRSR) mouse, fate-mapping lymphocytes responding to antigens at specific times and locations. Contrary to reports describing the ready egress of T cells out of the tumor, we find that intratumoral antigen signaling traps CD8+ T cells in the tumor. These clonal populations expand and become increasingly exhausted over time. By contrast, antigen-signaled regulatory T cell (Treg) clonal populations readily recirculate out of the tumor. Consequently, intratumoral antigen signaling acts as a gatekeeper to compartmentalize CD8+ T cell responses, even within the same clonotype, thus enabling exhausted T cells to remain confined to a specific tumor tissue site.
由于难以追踪淋巴细胞在抗原信号转导后的行为，免疫疗法的进展受到了阻碍。在这里，我们通过开发抗原受体信号转导报告（AGRSR）小鼠来评估活跃在肿瘤内的T细胞的行为，对在特定时间和位置对抗原做出反应的淋巴细胞进行命运图谱绘制。与T细胞可随时排出肿瘤的报道相反，我们发现瘤内抗原信号将CD8+ T细胞困在肿瘤内。随着时间的推移，这些克隆细胞群不断扩大并日益衰竭。相比之下，抗原信号调节性 T 细胞（Treg）克隆群很容易再循环到肿瘤外。因此，瘤内抗原信号起到了看门人的作用，将 CD8+ T 细胞反应分隔开来，即使在同一克隆类型中也是如此，从而使衰竭的 T 细胞局限于特定的肿瘤组织部位。
{"title":"Intratumoral antigen signaling traps CD8+ T cells to confine exhaustion to the tumor site","authors":"Munetomo Takahashi, Tsz Y. So, Vitalina Chamberlain-Evans, Robert Hughes, Juan Carlos Yam-Puc, Katarzyna Kania, Michelle Ruhle, Tiffeney Mann, Martijn J. Schuijs, Paul Coupland, Dean Naisbitt, Timotheus Y. F. Halim, Paul A. Lyons, Pietro Lio, Rahul Roychoudhuri, Klaus Okkenhaug, David J. Adams, Ken G. C. Smith, Duncan I. Jodrell, Michael A. Chapman, James E. D. Thaventhiran","doi":"10.1126/sciimmunol.ade2094","DOIUrl":"10.1126/sciimmunol.ade2094","url":null,"abstract":"<div >Immunotherapy advances have been hindered by difficulties in tracking the behaviors of lymphocytes after antigen signaling. Here, we assessed the behavior of T cells active within tumors through the development of the antigen receptor signaling reporter (AgRSR) mouse, fate-mapping lymphocytes responding to antigens at specific times and locations. Contrary to reports describing the ready egress of T cells out of the tumor, we find that intratumoral antigen signaling traps CD8<sup>+</sup> T cells in the tumor. These clonal populations expand and become increasingly exhausted over time. By contrast, antigen-signaled regulatory T cell (T<sub>reg</sub>) clonal populations readily recirculate out of the tumor. Consequently, intratumoral antigen signaling acts as a gatekeeper to compartmentalize CD8<sup>+</sup> T cell responses, even within the same clonotype, thus enabling exhausted T cells to remain confined to a specific tumor tissue site.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093251","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}
Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor–β (TGF-β) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-β signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of “stress memory.”
{"title":"Heart failure promotes multimorbidity through innate immune memory","authors":"Yukiteru Nakayama, Katsuhito Fujiu, Tsukasa Oshima, Jun Matsuda, Junichi Sugita, Takumi James Matsubara, Yuxiang Liu, Kohsaku Goto, Kunihiro Kani, Ryoko Uchida, Norifumi Takeda, Hiroyuki Morita, Yingda Xiao, Michiko Hayashi, Yujin Maru, Eriko Hasumi, Toshiya Kojima, Soh Ishiguro, Yusuke Kijima, Nozomu Yachie, Satoshi Yamazaki, Ryo Yamamoto, Fujimi Kudo, Mio Nakanishi, Atsushi Iwama, Ryoji Fujiki, Atsushi Kaneda, Osamu Ohara, Ryozo Nagai, Ichiro Manabe, Issei Komuro","doi":"10.1126/sciimmunol.ade3814","DOIUrl":"10.1126/sciimmunol.ade3814","url":null,"abstract":"<div >Patients with heart failure (HF) often experience repeated acute decompensation and develop comorbidities such as chronic kidney disease and frailty syndrome. Although this suggests pathological interaction among comorbidities, the mechanisms linking them are poorly understood. Here, we identified alterations in hematopoietic stem cells (HSCs) as a critical driver of recurrent HF and associated comorbidities. Bone marrow transplantation from HF-experienced mice resulted in spontaneous cardiac dysfunction and fibrosis in recipient mice, as well as increased vulnerability to kidney and skeletal muscle insults. HF enhanced the capacity of HSCs to generate proinflammatory macrophages. In HF mice, global chromatin accessibility analysis and single-cell RNA-seq showed that transforming growth factor–β (TGF-β) signaling was suppressed in HSCs, which corresponded with repressed sympathetic nervous activity in bone marrow. Transplantation of bone marrow from mice in which TGF-β signaling was inhibited similarly exacerbated cardiac dysfunction. Collectively, these results suggest that cardiac stress modulates the epigenome of HSCs, which in turn alters their capacity to generate cardiac macrophage subpopulations. This change in HSCs may be a common driver of repeated HF events and comorbidity by serving as a key carrier of “stress memory.”</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ade3814","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093294","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 : 2024-05-24DOI: 10.1126/sciimmunol.ade5705
Rui Chen, Elena Lukianova, Ina Schim van der Loeff, Jarmila Stremenova Spegarova, Joseph D.P. Willet, Kieran D. James, Edward J. Ryder, Helen Griffin, Hanna IJspeert, Akshada Gajbhiye, Frederic Lamoliatte, Jose L. Marin-Rubio, Lisa Woodbine, Henrique Lemos, David J. Swan, Valeria Pintar, Kamal Sayes, Elias R. Ruiz-Morales, Simon Eastham, David Dixon, Martin Prete, Elena Prigmore, Penny Jeggo, Joan Boyes, Andrew Mellor, Lei Huang, Mirjam van der Burg, Karin R. Engelhardt, Asbjørg Stray-Pedersen, Hans Christian Erichsen, Andrew R. Gennery, Matthias Trost, David J. Adams, Graham Anderson, Anna Lorenc, Gosia Trynka, Sophie Hambleton
Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 11 affected patients across four consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain–containing 3 (NUDCD3). Two infants had severe combined immunodeficiency with the complete absence of T and B cells (T -B- SCID), whereas nine showed classical features of Omenn syndrome (OS). Restricted antigen receptor gene usage by residual T lymphocytes suggested impaired V(D)J recombination. Patient cells showed reduced expression of NUDCD3 protein and diminished ability to support RAG-mediated recombination in vitro, which was associated with pathologic sequestration of RAG1 in the nucleoli. Although impaired V(D)J recombination in a mouse model bearing the homologous variant led to milder immunologic abnormalities, NUDCD3 is absolutely required for healthy T and B cell development in humans.
先天性 T 细胞发育异常是一种儿科急症，及时的治疗方法取决于分子诊断。在 4 个近亲血统的 11 名患者中，我们检测到了含 NudC 结构域的 3（NUDCD3）基因的单个有害错义变异的同源性。两名婴儿患有严重的联合免疫缺陷症，T 细胞和 B 细胞完全缺失（T -B- SCID），而九名婴儿则表现出典型的奥门综合征（OS）特征。残余T淋巴细胞的抗原受体基因使用受限，表明V（D）J重组受损。患者细胞的NUDCD3蛋白表达量减少，体外支持RAG介导的重组的能力减弱，这与核小体中RAG1的病理性固着有关。虽然在携带同源变异体的小鼠模型中，V（D）J 重组受损会导致较轻微的免疫异常，但 NUDCD3 绝对是人类 T 细胞和 B 细胞健康发育所必需的。
{"title":"NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome","authors":"Rui Chen, Elena Lukianova, Ina Schim van der Loeff, Jarmila Stremenova Spegarova, Joseph D.P. Willet, Kieran D. James, Edward J. Ryder, Helen Griffin, Hanna IJspeert, Akshada Gajbhiye, Frederic Lamoliatte, Jose L. Marin-Rubio, Lisa Woodbine, Henrique Lemos, David J. Swan, Valeria Pintar, Kamal Sayes, Elias R. Ruiz-Morales, Simon Eastham, David Dixon, Martin Prete, Elena Prigmore, Penny Jeggo, Joan Boyes, Andrew Mellor, Lei Huang, Mirjam van der Burg, Karin R. Engelhardt, Asbjørg Stray-Pedersen, Hans Christian Erichsen, Andrew R. Gennery, Matthias Trost, David J. Adams, Graham Anderson, Anna Lorenc, Gosia Trynka, Sophie Hambleton","doi":"10.1126/sciimmunol.ade5705","DOIUrl":"10.1126/sciimmunol.ade5705","url":null,"abstract":"<div >Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 11 affected patients across four consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain–containing 3 (<i>NUDCD3</i>)<i>.</i> Two infants had severe combined immunodeficiency with the complete absence of T and B cells (T<sup> -</sup>B<sup>-</sup> SCID), whereas nine showed classical features of Omenn syndrome (OS). Restricted antigen receptor gene usage by residual T lymphocytes suggested impaired V(D)J recombination. Patient cells showed reduced expression of NUDCD3 protein and diminished ability to support RAG-mediated recombination in vitro, which was associated with pathologic sequestration of RAG1 in the nucleoli. Although impaired V(D)J recombination in a mouse model bearing the homologous variant led to milder immunologic abnormalities, NUDCD3 is absolutely required for healthy T and B cell development in humans.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ade5705","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141093322","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 : 2024-05-17DOI: 10.1126/sciimmunol.adi5374
Blanda Di Luccia, Martina Molgora, Darya Khantakova, Natalia Jaeger, Hao-Wei Chang, Rafael S. Czepielewski, Beth A. Helmink, Emily J. Onufer, José L. Fachi, Bishan Bhattarai, Tihana Trsan, Patrick F. Rodrigues, JinChao Hou, Jennifer K. Bando, Cristiane Sécca da Silva, Marina Cella, Susan Gilfillan, Robert D. Schreiber, Jeffrey I. Gordon, Marco Colonna
The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti–programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti–PD-1. Here, we found that anti–PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti–PD-1–mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti–PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.
{"title":"TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti–PD-1 tumor immunotherapy","authors":"Blanda Di Luccia, Martina Molgora, Darya Khantakova, Natalia Jaeger, Hao-Wei Chang, Rafael S. Czepielewski, Beth A. Helmink, Emily J. Onufer, José L. Fachi, Bishan Bhattarai, Tihana Trsan, Patrick F. Rodrigues, JinChao Hou, Jennifer K. Bando, Cristiane Sécca da Silva, Marina Cella, Susan Gilfillan, Robert D. Schreiber, Jeffrey I. Gordon, Marco Colonna","doi":"10.1126/sciimmunol.adi5374","DOIUrl":"10.1126/sciimmunol.adi5374","url":null,"abstract":"<div >The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti–programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti–PD-1. Here, we found that anti–PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of <i>Ruminococcus gnavus</i> in the gut microbiota. Gavage of wild-type mice with <i>R. gnavus</i> enhanced anti–PD-1–mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4<sup>+</sup> T cells to the tumor bed. Thus, TREM2 remotely controls anti–PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with <i>R. gnavus</i> emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":24.8,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953857","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：