Science Immunology最新文献

{"title":"Trogocytosis of chimeric antigen receptors between T cells is regulated by their transmembrane domains.","authors":"Stefano Barbera, Matthijs J A Schuiling, Nathaniel A Sanjaya, Ilkka Pietilä, Tina Sarén, Magnus Essand, Anna Dimberg","doi":"10.1126/sciimmunol.ado2054","DOIUrl":"10.1126/sciimmunol.ado2054","url":null,"abstract":"<p><p>Trogocytosis is an exchange of membrane-associated molecules between cells that can either halt or boost immune responses. However, the mechanism that regulates trogocytosis in T cells and its consequences are not yet clear. Here, we demonstrate that T cells can exchange chimeric antigen receptors (CARs) by trogocytosis, thereby arming recipient T cells with the capacity to respond to tumor antigens by up-regulating proteins associated with a cytotoxic response and killing of target cells. We demonstrate that although trogocytosis is dependent on cell-cell contact, the exchange of a specific cell membrane protein does not require a cognate binding partner on the surface of recipient cells. Instead, the probability that a protein is exchanged by trogocytosis is determined by its transmembrane domain. This finding opens new avenues for modulating this process in CAR-T cells.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":"eado2054"},"PeriodicalIF":17.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070795","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}

{"title":"Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression.","authors":"Catarina Gago da Graça, Amania A Sheikh, Dane M Newman, Lifen Wen, Sining Li, Jian Shen, Yuqi Zhang, Sarah S Gabriel, David Chisanga, Justine Seow, Annika Poch, Lisa Rausch, Minh-Hanh T Nguyen, Jayendra Singh, Chun-Hsi Su, Leonie A Cluse, Carlson Tsui, Thomas N Burn, Simone L Park, Bianca Von Scheidt, Laura K Mackay, Ajithkumar Vasanthakumar, David Bending, Wei Shi, Weiguo Cui, Jan Schröder, Ricky W Johnstone, Axel Kallies, Daniel T Utzschneider","doi":"10.1126/sciimmunol.adn1945","DOIUrl":"10.1126/sciimmunol.adn1945","url":null,"abstract":"<p><p>Stem-like T cells are attractive immunotherapeutic targets in patients with cancer given their ability to proliferate and differentiate into effector progeny. Thus, identifying T cells with enhanced stemness and understanding their developmental requirements are of broad clinical and therapeutic interest. Here, we demonstrate that during acute infection, the transcriptional regulator inhibitor of DNA binding 3 (ID3) identifies stem-like T cells that are uniquely adapted to generate precursors of exhausted T (Tpex) cells in response to chronic infection or cancer. Expression of ID3 itself enables Tpex cells to sustain T cell responses in chronic infection or cancer, whereas loss of ID3 results in impaired maintenance of CD8 T cell immunity. Furthermore, we demonstrate that interleukin-1 (IL-1) family members, including IL-36β and IL-18, promote the generation of ID3⁺ T cells that mediate superior tumor control. Overall, we identify ID3 as a common denominator of stem-like T cells in both acute and chronic infections that is specifically required to sustain T cell responses to chronic stimulation.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":"eadn1945"},"PeriodicalIF":17.6,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070776","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}

{"title":"The meninges host a distinct compartment of regulatory T cells that preserves brain homeostasis","authors":"Miguel Marin-Rodero,&nbsp;Elisa Cintado,&nbsp;Alec J. Walker,&nbsp;Teshika Jayewickreme,&nbsp;Felipe A. Pinho-Ribeiro,&nbsp;Quentin Richardson,&nbsp;Ruaidhrí Jackson,&nbsp;Isaac M. Chiu,&nbsp;Christophe Benoist,&nbsp;Beth Stevens,&nbsp;José Luís Trejo,&nbsp;Diane Mathis","doi":"10.1126/sciimmunol.adu2910","DOIUrl":"10.1126/sciimmunol.adu2910","url":null,"abstract":"<div >Our understanding of the meningeal immune system has recently burgeoned, particularly regarding how innate and adaptive effector cells are mobilized to meet brain challenges. However, information on how meningeal immunocytes guard brain homeostasis in healthy individuals remains limited. This study highlights the heterogeneous, polyfunctional regulatory T cell (T_reg) compartment in the meninges. A T_reg subtype specialized in controlling interferon-γ (IFN-γ) responses and another dedicated to regulating follicular B cell responses were substantial components of this compartment. Accordingly, punctual T_reg ablation rapidly unleashed IFN-γ production by meningeal lymphocytes, unlocked access to the brain parenchyma, and altered meningeal B cell profiles. Distally, the hippocampus assumed a reactive state, with morphological and transcriptional changes in multiple glial cell types. Within the dentate gyrus, neural stem cells underwent more death and were blocked from further differentiation, which coincided with impairments in short-term spatial-reference memory. Thus, meningeal T_regs are a multifaceted safeguard of brain homeostasis at steady state.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 104","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adu2910","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053272","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}

{"title":"Coordinated immune networks in leukemia bone marrow microenvironments distinguish response to cellular therapy","authors":"Katie Maurer,&nbsp;Cameron Y. Park,&nbsp;Shouvik Mani,&nbsp;Mehdi Borji,&nbsp;Florian Raths,&nbsp;Kenneth H. Gouin III,&nbsp;Livius Penter,&nbsp;Yinuo Jin,&nbsp;Jia Yi Zhang,&nbsp;Crystal Shin,&nbsp;James R. Brenner,&nbsp;Jackson Southard,&nbsp;Sachi Krishna,&nbsp;Wesley Lu,&nbsp;Haoxiang Lyu,&nbsp;Domenic Abbondanza,&nbsp;Chanell Mangum,&nbsp;Lars Rønn Olsen,&nbsp;Michael J. Lawson,&nbsp;Martin Fabani,&nbsp;Donna S. Neuberg,&nbsp;Pavan Bachireddy,&nbsp;Eli N. Glezer,&nbsp;Samouil L. Farhi,&nbsp;Shuqiang Li,&nbsp;Kenneth J. Livak,&nbsp;Jerome Ritz,&nbsp;Robert J. Soiffer,&nbsp;Catherine J. Wu,&nbsp;Elham Azizi","doi":"10.1126/sciimmunol.adr0782","DOIUrl":"10.1126/sciimmunol.adr0782","url":null,"abstract":"<div >Understanding how intratumoral immune populations coordinate antitumor responses after therapy can guide treatment prioritization. We systematically analyzed an established immunotherapy, donor lymphocyte infusion (DLI), by assessing 348,905 single-cell transcriptomes from 74 longitudinal bone marrow samples of 25 patients with relapsed leukemia; a subset was evaluated by both protein- and transcriptome-based spatial analysis. In acute myeloid leukemia (AML) DLI responders, we identified clonally expanded <i>ZNF683</i>⁺ CD8⁺ cytotoxic T lymphocytes with in vitro specificity for patient-matched AML. These cells originated primarily from the DLI product and appeared to coordinate antitumor immune responses through interaction with diverse immune cell types within the marrow microenvironment. Nonresponders lacked this cross-talk and had cytotoxic T lymphocytes with elevated <i>TIGIT</i> expression. Our study identifies recipient bone marrow microenvironment differences as a determinant of an effective antileukemia response and opens opportunities to modulate cellular therapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adr0782","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030938","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}

{"title":"Human naïve B cells recognize prepandemic influenza virus hemagglutinins","authors":"Jared Feldman,&nbsp;Ana Sofia Ferreira Ramos,&nbsp;Mya Vu,&nbsp;Daniel P. Maurer,&nbsp;Victoria C. Rosado,&nbsp;Daniel Lingwood,&nbsp;Goran Bajic,&nbsp;Aaron G. Schmidt","doi":"10.1126/sciimmunol.ado9572","DOIUrl":"10.1126/sciimmunol.ado9572","url":null,"abstract":"<div >Understanding the naïve B cell repertoire and its specificity for potential zoonotic threats, such as the highly pathogenic avian influenza (HPAI) H5Nx viruses, may allow prediction of infection- or vaccine-specific responses. However, this naïve repertoire and the possibility to respond to emerging, prepandemic viruses are largely undetermined. Here, we profiled naïve B cell reactivity against a prototypical HPAI H5 hemagglutinin (HA), the major target of antibody responses. We found that the frequency of H5-specific human naïve B cells targeting the HA “head” domain was increased relative to cross-reactive B cells to a circulating seasonal H1N1 strain. We classified the isolated monoclonal antibodies (mAbs) by the HA epitopes engaged and found that selected mAbs neutralized H5N1 at germline. We determined a cryo–electron microscopic structure of one mAb in complex with H5 HA to define its epitope. Our study defines the naïve human B cell repertoire recognizing a potentially zoonotic HPAI.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.ado9572","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030939","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}

{"title":"Anti–immune complex antibodies are elicited during repeated immunization with HIV Env immunogens","authors":"Sharidan Brown,&nbsp;Aleksandar Antanasijevic,&nbsp;Leigh M. Sewall,&nbsp;Daniel Montiel Garcia,&nbsp;Philip J. M. Brouwer,&nbsp;Rogier W. Sanders,&nbsp;Andrew B. Ward","doi":"10.1126/sciimmunol.adp5218","DOIUrl":"10.1126/sciimmunol.adp5218","url":null,"abstract":"<div >Vaccination strategies against HIV-1 aim to elicit broadly neutralizing antibodies (bnAbs) using prime-boost regimens with HIV envelope (Env) immunogens. Epitope mapping has shown that early antibody responses are directed to easily accessible nonneutralizing epitopes on Env instead of bnAb epitopes. Autologously neutralizing antibody responses appear upon boosting, once immunodominant epitopes are saturated. Here, we use electron microscopy–based polyclonal epitope mapping (EMPEM) to elucidate how repeated immunization with HIV Env SOSIP immunogens results in the generation of Ab2α anti-idiotypic antibodies in rabbits and rhesus macaques. We present the structures of six anti–immune complex antibodies and find that they target idiotopes composed of framework regions of antibodies bound to Env. Examination of cryo–electron microscopy density enabled prediction of sequences for an anti–immune complex antibody, the paratope of which is enriched with aromatic amino acids. This work sheds light on current vaccine development efforts for HIV, as well as for other pathogens in which repeated exposure to antigen is required.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp5218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987476","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}

{"title":"Architects of immunity: How dendritic cells shape CD8+ T cell fate in cancer","authors":"Vidit Bhandarkar,&nbsp;Teresa Dinter,&nbsp;Stefani Spranger","doi":"10.1126/sciimmunol.adf4726","DOIUrl":"10.1126/sciimmunol.adf4726","url":null,"abstract":"<div >Immune responses against cancer are dominated by T cell exhaustion and dysfunction. Recent advances have underscored the critical role of early priming interactions in establishing T cell fates. In this review, we explore the importance of dendritic cell (DC) signals in specifying CD8⁺ T cell fates in cancer, drawing on insights from acute and chronic viral infection models. We highlight the role of DCs in lymph nodes and tumors in maintaining stem-like CD8⁺ T cells, which are critical for durable antitumor immune responses. Understanding how CD8⁺ T cell fates are determined will enable the rational design of immunotherapies, particularly therapeutic cancer vaccines, that can modulate DC–T cell interactions to generate beneficial CD8⁺ T cell fates.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987475","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}

{"title":"Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis","authors":"Cody Elkins,&nbsp;Chengyu Ye,&nbsp;Pulavendran Sivasami,&nbsp;Roy Mulpur,&nbsp;Pamela P. Diaz-Saldana,&nbsp;Amy Peng,&nbsp;Miaoer Xu,&nbsp;Yeun-po Chiang,&nbsp;Samara Moll,&nbsp;Dormarie E. Rivera-Rodriguez,&nbsp;Luisa Cervantes-Barragan,&nbsp;Tuoqi Wu,&nbsp;Byron B. Au-Yeung,&nbsp;Christopher D. Scharer,&nbsp;Mandy L. Ford,&nbsp;Haydn Kissick,&nbsp;Chaoran Li","doi":"10.1126/sciimmunol.adl4909","DOIUrl":"10.1126/sciimmunol.adl4909","url":null,"abstract":"<div >Regulatory T cells (T_regs) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT T_regs under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2^hi VAT T_reg subsets. T_reg-specific deletion of <i>Srebf2</i>, the master regulator of cholesterol homeostasis, selectively reduced ST2^hi VAT T_regs, increasing VAT inflammation and insulin resistance. Single-cell RNA/T cell receptor (TCR) sequencing revealed a specific loss and reduced clonal expansion of ST2^hi VAT T_reg subsets after <i>Srebf2</i> deletion. <i>Srebf2</i>-mediated cholesterol homeostasis potentiated strong TCR signaling, which preferentially promoted ST2^hi VAT T_reg accumulation. However, long-term high-fat diet feeding disrupted VAT T_reg cholesterol homeostasis and impaired clonal expansion of the ST2^hi subset. Restoring T_reg cholesterol homeostasis rescued VAT T_reg accumulation in obese mice, suggesting that modulation of cholesterol homeostasis could be a promising strategy for T_reg-targeted therapies in obesity-associated metabolic diseases.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939926","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}

{"title":"TSLP acts on regulatory T cells to maintain their identity and limit allergic inflammation","authors":"Rama K. Gurram,&nbsp;Peng Li,&nbsp;Jangsuk Oh,&nbsp;Xi Chen,&nbsp;Rosanne Spolski,&nbsp;Xianglan Yao,&nbsp;Jian-Xin Lin,&nbsp;Suyasha Roy,&nbsp;Matthew J. Liao,&nbsp;Chengyu Liu,&nbsp;Zu-Xi Yu,&nbsp;Stewart J. Levine,&nbsp;Jinfang Zhu,&nbsp;Warren J. Leonard","doi":"10.1126/sciimmunol.adk0073","DOIUrl":"10.1126/sciimmunol.adk0073","url":null,"abstract":"<div >Thymic stromal lymphopoietin (TSLP) is a type I cytokine that promotes allergic responses and mediates type 2 immunity. A balance between effector T cells (T_effs), which drive the immune response, and regulatory T cells (T_regs), which suppress the response, is required for proper immune homeostasis. Here, we report that TSLP differentially acts on T_effs versus T_regs to balance type 2 immunity. As expected, deletion of TSLP receptor (TSLPR) on all T cells (<i>Cd4</i>^Cre<i>Crlf2</i>^fl/fl mice) resulted in lower numbers of T helper 2 (T_H2) cells and diminished ovalbumin-induced airway inflammation, but selective deletion of TSLPR on T_regs (<i>Foxp3</i>^{<i>YFP</i>-Cre/Y}<i>Crlf2</i>^fl/fl mice) resulted in increased interleukin-5 (IL-5)– and IL-13–secreting T_H2 cells and lung eosinophilia. Moreover, TSLP augmented the expression of factors that stabilize T_regs. During type 2 immune responses, TSLPR-deficient T_regs acquired T_H2-like properties, with augmented GATA3 expression and secretion of IL-13. TSLP not only is a driver of T_H2 effector cells but also acts in a negative feedback loop, thus promoting the ability of T_regs to limit allergic inflammation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939924","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}

{"title":"Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature","authors":"Marita Bosticardo,&nbsp;Kerry Dobbs,&nbsp;Ottavia M. Delmonte,&nbsp;Andrew J. Martins,&nbsp;Francesca Pala,&nbsp;Tomoki Kawai,&nbsp;Heather Kenney,&nbsp;Gloria Magro,&nbsp;Lindsey B. Rosen,&nbsp;Yasuhiro Yamazaki,&nbsp;Hsin-Hui Yu,&nbsp;Enrica Calzoni,&nbsp;Yu Nee Lee,&nbsp;Can Liu,&nbsp;Jennifer Stoddard,&nbsp;Julie Niemela,&nbsp;Danielle Fink,&nbsp;Riccardo Castagnoli,&nbsp;Meredith Ramba,&nbsp;Aristine Cheng,&nbsp;Deanna Riley,&nbsp;Vasileios Oikonomou,&nbsp;Elana Shaw,&nbsp;Brahim Belaid,&nbsp;Sevgi Keles,&nbsp;Waleed Al-Herz,&nbsp;Caterina Cancrini,&nbsp;Cristina Cifaldi,&nbsp;Safa Baris,&nbsp;Svetlana Sharapova,&nbsp;Catharina Schuetz,&nbsp;Andrew R. Gennery,&nbsp;Alexandra F. Freeman,&nbsp;Raz Somech,&nbsp;Sharon Choo,&nbsp;Silvia C. Giliani,&nbsp;Tayfun Güngör,&nbsp;Daniel Drozdov,&nbsp;Isabelle Meyts,&nbsp;Despina Moshous,&nbsp;Benedicte Neven,&nbsp;Roshini S. Abraham,&nbsp;Aisha El-Marsafy,&nbsp;Maria Kanariou,&nbsp;Alejandra King,&nbsp;Francesco Licciardi,&nbsp;Mario E. Cruz-Muñoz,&nbsp;Paolo Palma,&nbsp;Cecilia Poli,&nbsp;Mehdi Adeli,&nbsp;Mattia Algeri,&nbsp;Fayhan J. Alroqi,&nbsp;Paul Bastard,&nbsp;Jenna R. E. Bergerson,&nbsp;Claire Booth,&nbsp;Ana Brett,&nbsp;Siobhan O. Burns,&nbsp;Manish J. Butte,&nbsp;Nurcicek Padem,&nbsp;M. Teresa de la Morena,&nbsp;Ghassan Dbaibo,&nbsp;Suk See de Ravin,&nbsp;Dimana Dimitrova,&nbsp;Reda Djidjik,&nbsp;Mayra B. Dorna,&nbsp;Cullen M. Dutmer,&nbsp;Reem Elfeky,&nbsp;Fabio Facchetti,&nbsp;Ramsay L. Fuleihan,&nbsp;Raif S. Geha,&nbsp;Luis I. Gonzalez-Granado,&nbsp;Liis Haljasmägi,&nbsp;Hanadys Ale,&nbsp;Anthony Hayward,&nbsp;Anna M. Hifanova,&nbsp;Winnie Ip,&nbsp;Blanka Kaplan,&nbsp;Neena Kapoor,&nbsp;Elif Karakoc-Aydiner,&nbsp;Jaanika Kärner,&nbsp;Michael D. Keller,&nbsp;Blachy J. Dávila Saldaña,&nbsp;Ayça Kiykim,&nbsp;Taco W. Kuijpers,&nbsp;Elena E. Kuznetsova,&nbsp;Elena A. Latysheva,&nbsp;Jennifer W. Leiding,&nbsp;Franco Locatelli,&nbsp;Guisela Alva-Lozada,&nbsp;Christine McCusker,&nbsp;Fatih Celmeli,&nbsp;Megan Morsheimer,&nbsp;Ahmet Ozen,&nbsp;Nima Parvaneh,&nbsp;Srdjan Pasic,&nbsp;Alessandro Plebani,&nbsp;Kahn Preece,&nbsp;Susan Prockop,&nbsp;Inga S. Sakovich,&nbsp;Elena E. Starkova,&nbsp;Troy Torgerson,&nbsp;James Verbsky,&nbsp;Jolan E. Walter,&nbsp;Brant Ward,&nbsp;Elizabeth L. Wisner,&nbsp;Deborah Draper,&nbsp;Katherine Myint-Hpu,&nbsp;Pooi M. Truong,&nbsp;Michail S. Lionakis,&nbsp;Morgan B. Similuk,&nbsp;Centralized Sequencing Program Group§§,&nbsp;Magdalena A. Walkiewicz,&nbsp;Amy Klion,&nbsp;Steven M. Holland,&nbsp;Cihan Oguz,&nbsp;Dusan Bogunovic,&nbsp;Kai Kisand,&nbsp;Helen C. Su,&nbsp;John S. Tsang,&nbsp;Douglas Kuhns,&nbsp;Anna Villa,&nbsp;Sergio D. Rosenzweig,&nbsp;Stefania Pittaluga,&nbsp;Luigi D. Notarangelo","doi":"10.1126/sciimmunol.adq1697","DOIUrl":"10.1126/sciimmunol.adq1697","url":null,"abstract":"<div >Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of <i>RAG</i>-mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic <i>RAG</i> variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (T_H2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage–specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 103","pages":""},"PeriodicalIF":17.6,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adq1697","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056081","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}