Science Immunology最新文献

{"title":"Expansion of tumor-reactive CD8+ T cell clonotypes occurs in the spleen in response to immune checkpoint blockade","authors":"Duncan M. Morgan,&nbsp;Brendan L. Horton,&nbsp;Vidit Bhandarkar,&nbsp;Richard Van,&nbsp;Teresa Dinter,&nbsp;Maria Zagorulya,&nbsp;J. Christopher Love,&nbsp;Stefani Spranger","doi":"10.1126/sciimmunol.adi3487","DOIUrl":"10.1126/sciimmunol.adi3487","url":null,"abstract":"<div >Immune checkpoint blockade (ICB) enhances T cell responses against cancer, leading to long-term survival in a fraction of patients. CD8⁺ T cell differentiation in response to chronic antigen stimulation is highly complex, and it remains unclear precisely which T cell differentiation states at which anatomic sites are critical for the response to ICB. We identified an intermediate-exhausted population in the white pulp of the spleen that underwent substantial expansion in response to ICB and gave rise to tumor-infiltrating clonotypes. Increased systemic antigen redirected differentiation of this population toward a more circulatory exhausted KLR state, whereas a lack of cross-presented tumor antigen reduced its differentiation in the spleen. An analogous population of exhausted KLR CD8⁺ T cells in human blood samples exhibited diminished tumor-trafficking ability. Collectively, our data demonstrate the critical role of antigen density within the spleen for the differentiation and expansion of T cell clonotypes in response to ICB.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231190","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":"CD4+ T cells with convergent TCR recombination reprogram stroma and halt tumor progression in adoptive therapy","authors":"Steven P. Wolf,&nbsp;Matthias Leisegang,&nbsp;Madeline Steiner,&nbsp;Veronika Wallace,&nbsp;Kazuma Kiyotani,&nbsp;Yifei Hu,&nbsp;Leonie Rosenberger,&nbsp;Jun Huang,&nbsp;Karin Schreiber,&nbsp;Yusuke Nakamura,&nbsp;Andrea Schietinger,&nbsp;Hans Schreiber","doi":"10.1126/sciimmunol.adp6529","DOIUrl":"10.1126/sciimmunol.adp6529","url":null,"abstract":"<div >Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4⁺ T cells (CD4TCRs) from tumor-bearing hosts can be exploited for adoptive TCR therapy. We focused on CD4TCRs targeting an autochthonous mutant neoantigen that is only presented by stroma surrounding the MHC class II–negative cancer cells. The 11 most common tetramer-sorted CD4TCRs were tested using TCR-engineered CD4⁺ T cells. Three TCRs were characterized by convergent recombination for which multiple T cell clonotypes differed in their nucleotide sequences but encoded identical TCR α and β chains. These preferentially selected TCRs destroyed tumors equally well and halted progression through reprogramming of the tumor stroma. TCRs represented by single T cell clonotypes were similarly effective only if they shared CDR elements with preferentially selected TCRs in both α and β chains. Selecting candidate TCRs on the basis of these characteristics can help identify TCRs that are potentially therapeutically effective.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231172","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":"MAIT cell heterogeneity across paired human tissues reveals specialization of distinct regulatory and enhanced effector profiles","authors":"Tobias Kammann,&nbsp;Curtis Cai,&nbsp;Takuya Sekine,&nbsp;Elli Mouchtaridi,&nbsp;Caroline Boulouis,&nbsp;Vera Nilsén,&nbsp;Olga Rivera Ballesteros,&nbsp;Thomas R. Müller,&nbsp;Yu Gao,&nbsp;Elisa J. M. Raineri,&nbsp;Akhirunnesa Mily,&nbsp;Sarah Adamo,&nbsp;Christian Constantz,&nbsp;Julia Niessl,&nbsp;Whitney Weigel,&nbsp;Efthymia Kokkinou,&nbsp;Christopher Stamper,&nbsp;Anne Marchalot,&nbsp;John Bassett,&nbsp;Sabrina Ferreira,&nbsp;Inga Rødahl,&nbsp;Nicole Wild,&nbsp;Demi Brownlie,&nbsp;Chris Tibbitt,&nbsp;Jeffrey Y. W. Mak,&nbsp;David P. Fairlie,&nbsp;Edwin Leeansyah,&nbsp;Jakob Michaelsson,&nbsp;Nicole Marquardt,&nbsp;Jenny Mjösberg,&nbsp;Carl Jorns,&nbsp;Marcus Buggert,&nbsp;Johan K. Sandberg","doi":"10.1126/sciimmunol.adn2362","DOIUrl":"10.1126/sciimmunol.adn2362","url":null,"abstract":"<div >Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize microbial riboflavin pathway metabolites presented by evolutionarily conserved MR1 molecules. We explored the human MAIT cell compartment across organ donor–matched blood, barrier, and lymphoid tissues. MAIT cell population size was donor dependent with distinct tissue compartmentalization patterns and adaptations: Intestinal CD103⁺ resident MAIT cells presented an immunoregulatory CD39^highCD27^low profile, whereas MAIT cells expressing NCAM1/CD56 dominated in the liver and exhibited enhanced effector capacity with elevated response magnitude and polyfunctionality. Both intestinal CD39^high and hepatic CD56⁺ adaptations accumulated with donor age. CD56⁺ MAIT cells displayed limited T cell receptor–repertoire breadth, elevated MR1 binding, and a transcriptional profile skewed toward innate activation pathways. Furthermore, CD56 was dynamically up-regulated to a persistent steady-state equilibrium after exposure to antigen or IL-7. In summary, we demonstrate functional heterogeneity and tissue site adaptation in resident MAIT cells across human barrier tissues with distinct regulatory and effector signatures.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143376","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":"IgE plasma cells are transcriptionally and functionally distinct from other isotypes","authors":"Andrea Vecchione,&nbsp;Joseph C. Devlin,&nbsp;Carley Tasker,&nbsp;Venkat Raman Ramnarayan,&nbsp;Paul Haase,&nbsp;Eva Conde,&nbsp;Devin Srivastava,&nbsp;Gurinder S. Atwal,&nbsp;Pierre Bruhns,&nbsp;Andrew J. Murphy,&nbsp;Matthew A. Sleeman,&nbsp;Andre Limnander,&nbsp;Wei Keat Lim,&nbsp;Seblewongel Asrat,&nbsp;Jamie M. Orengo","doi":"10.1126/sciimmunol.adm8964","DOIUrl":"10.1126/sciimmunol.adm8964","url":null,"abstract":"<div >Understanding the phenotypic and transcriptional signature of immunoglobulin E (IgE)–producing cells is fundamental to plasma cell (PC) biology and development of therapeutic interventions for allergy. Here, using a mouse model of intranasal house dust mite (HDM) exposure, we showed that short-lived IgE PCs emerge in lung draining lymph nodes (dLNs) during early exposure (&lt;3 weeks) and long-lived IgE PCs accumulate in the bone marrow (BM) with prolonged exposure (&gt;7 weeks). IgE PCs had distinct surface and gene expression profiles in these different tissues compared with other Ig isotypes. IgE BMPCs up-regulated genes associated with prosurvival and BM homing, whereas IgE dLN PCs expressed genes associated with recent class switching and differentiation. IgE PCs also exhibited higher expression of endoplasmic reticulum (ER) stress and protein coding genes and higher antibody secretion rate when compared with IgG1. Overall, this study highlights the unique developmental path and transcriptional signature of short-lived and long-lived IgE PCs.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adm8964","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143375","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":"Convergent evolution of monocyte differentiation in adult skin instructs Langerhans cell identity","authors":"Anna Appios,&nbsp;James Davies,&nbsp;Sofia Sirvent,&nbsp;Stephen Henderson,&nbsp;Sébastien Trzebanski,&nbsp;Johannes Schroth,&nbsp;Morven L. Law,&nbsp;Inês Boal Carvalho,&nbsp;Marlene Magalhaes Pinto,&nbsp;Cyril Carvalho,&nbsp;Howard Yuan-Hao Kan,&nbsp;Shreya Lovlekar,&nbsp;Christina Major,&nbsp;Andres Vallejo,&nbsp;Nigel J. Hall,&nbsp;Michael Ardern-Jones,&nbsp;Zhaoyuan Liu,&nbsp;Florent Ginhoux,&nbsp;Sian M. Henson,&nbsp;Rebecca Gentek,&nbsp;Elaine Emmerson,&nbsp;Steffen Jung,&nbsp;Marta E. Polak,&nbsp;Clare L. Bennett","doi":"10.1126/sciimmunol.adp0344","DOIUrl":"10.1126/sciimmunol.adp0344","url":null,"abstract":"<div >Langerhans cells (LCs) are distinct among phagocytes, functioning both as embryo-derived, tissue-resident macrophages in skin innervation and repair and as migrating professional antigen-presenting cells, a function classically assigned to dendritic cells (DCs). Here, we demonstrate that both intrinsic and extrinsic factors imprint this dual identity. Using ablation of embryo-derived LCs in the murine adult skin and tracking differentiation of incoming monocyte-derived replacements, we found intrinsic intraepidermal heterogeneity. We observed that ontogenically distinct monocytes give rise to LCs. Within the epidermis, Jagged-dependent activation of Notch signaling, likely within the hair follicle niche, provided an initial site of LC commitment before metabolic adaptation and survival of monocyte-derived LCs. In the human skin, embryo-derived LCs in newborns retained transcriptional evidence of their macrophage origin, but this was superseded by DC-like immune modules after postnatal expansion. Thus, adaptation to adult skin niches replicates conditioning of LC at birth, permitting repair of the embryo-derived LC network.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143374","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":"Pre-vax metabolic clues: Cracking the code to a better dengue vaccine","authors":"Fahima Akther,&nbsp;David R. Martinez","doi":"10.1126/sciimmunol.ads7640","DOIUrl":"10.1126/sciimmunol.ads7640","url":null,"abstract":"<div >Multi-omic analysis deciphers the impact of cell-intrinsic and systemic metabolomes on dengue vaccination immunogenicity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143377","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":"When a double negative is not a positive: Autoantibodies against IL-10 in patients with inflammatory bowel disease","authors":"Colleen M. Noviello","doi":"10.1126/sciimmunol.ads7642","DOIUrl":"10.1126/sciimmunol.ads7642","url":null,"abstract":"<div >IL-10 autoantibodies are detected in two patients with severe inflammatory bowel disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143378","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":"Immunization with germ line–targeting SOSIP trimers elicits broadly neutralizing antibody precursors in infant macaques","authors":"Ashley N. Nelson,&nbsp;Xiaoying Shen,&nbsp;Sravani Vekatayogi,&nbsp;Shiyu Zhang,&nbsp;Gabriel Ozorowski,&nbsp;Maria Dennis,&nbsp;Leigh M. Sewall,&nbsp;Emma Milligan,&nbsp;Dominique Davis,&nbsp;Kaitlyn A. Cross,&nbsp;Yue Chen,&nbsp;Jelle van Schooten,&nbsp;Joshua Eudailey,&nbsp;John Isaac,&nbsp;Saad Memon,&nbsp;Carolyn Weinbaum,&nbsp;Hongmei Gao,&nbsp;Sherry Stanfield-Oakley,&nbsp;Alliyah Byrd,&nbsp;Suni Chutkan,&nbsp;Stella Berendam,&nbsp;Kenneth Cronin,&nbsp;Anila Yasmeen,&nbsp;S. Munir Alam,&nbsp;Celia C. LaBranche,&nbsp;Kenneth Rogers,&nbsp;Lisa Shirreff,&nbsp;Albert Cupo,&nbsp;Ronald Derking,&nbsp;Francois Villinger,&nbsp;Per Johan Klasse,&nbsp;Guido Ferrari,&nbsp;Wilton B. Williams,&nbsp;Michael G. Hudgens,&nbsp;Andrew B. Ward,&nbsp;David C. Montefiori,&nbsp;Koen K. A. Van Rompay,&nbsp;Kevin Wiehe,&nbsp;John P. Moore,&nbsp;Rogier W. Sanders,&nbsp;Kristina De Paris,&nbsp;Sallie R. Permar","doi":"10.1126/sciimmunol.adm7097","DOIUrl":"10.1126/sciimmunol.adm7097","url":null,"abstract":"<div >Adolescents are a growing population of people living with HIV. The period between weaning and sexual debut presents a low-risk window for HIV acquisition, making early childhood an ideal time for implementing an immunization regimen. Because the elicitation of broadly neutralizing antibodies (bnAbs) is critical for an effective HIV vaccine, our goal was to assess the ability of a bnAb B cell lineage–designed HIV envelope SOSIP (protein stabilized by a disulfide bond between gp120-gp41—named “SOS”—and an isoleucine-to-proline point mutation—named “IP”—at residue 559) to induce precursor CD4 binding site (CD4bs)–targeting bnAbs in early life. Infant rhesus macaques received either a BG505 SOSIP, based on the infant BG505 transmitted/founder virus, or the CD4bs germ line–targeting BG505 SOSIP GT1.1 (<i>n</i> = 5 per group). Although both strategies induced durable, high-magnitude plasma autologous virus neutralization responses, only GT1.1-immunized infants (<i>n</i> = 3 of 5) exhibited VRC01-like CD4bs bnAb precursor development. Thus, a multidose immunization regimen with bnAb lineage–designed SOSIPs shows promise for inducing early B cell responses with the potential to mature into protective HIV bnAbs before sexual debut.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100585","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":"The promise of priming precursors: Advances in inducing CD4 binding site–directed HIV broadly neutralizing antibodies","authors":"Rama Rao Amara","doi":"10.1126/sciimmunol.adq8862","DOIUrl":"10.1126/sciimmunol.adq8862","url":null,"abstract":"<div >HIV envelope immunogen designed to activate germline B cell precursors of CD4 binding site–specific neutralizing antibodies shows promise in monkeys.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100525","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":"Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site","authors":"Tom G. Caniels,&nbsp;Max Medina-Ramìrez,&nbsp;Shiyu Zhang,&nbsp;Sven Kratochvil,&nbsp;Yuejiao Xian,&nbsp;Ja-Hyun Koo,&nbsp;Ronald Derking,&nbsp;Jakob Samsel,&nbsp;Jelle van Schooten,&nbsp;Simone Pecetta,&nbsp;Edward Lamperti,&nbsp;Meng Yuan,&nbsp;María Ríos Carrasco,&nbsp;Iván del Moral Sánchez,&nbsp;Joel D. Allen,&nbsp;Joey H. Bouhuijs,&nbsp;Anila Yasmeen,&nbsp;Thomas J. Ketas,&nbsp;Jonne L. Snitselaar,&nbsp;Tom P. L. Bijl,&nbsp;Isabel Cuella Martin,&nbsp;Jonathan L. Torres,&nbsp;Albert Cupo,&nbsp;Lisa Shirreff,&nbsp;Kenneth Rogers,&nbsp;Rosemarie D. Mason,&nbsp;Mario Roederer,&nbsp;Kelli M. Greene,&nbsp;Hongmei Gao,&nbsp;Catarina Mendes Silva,&nbsp;Isabel J. L. Baken,&nbsp;Ming Tian,&nbsp;Frederick W. Alt,&nbsp;Bali Pulendran,&nbsp;Michael S. Seaman,&nbsp;Max Crispin,&nbsp;Marit J. van Gils,&nbsp;David C. Montefiori,&nbsp;Adrian B. McDermott,&nbsp;François J. Villinger,&nbsp;Richard A. Koup,&nbsp;John P. Moore,&nbsp;Per Johan Klasse,&nbsp;Gabriel Ozorowski,&nbsp;Facundo D. Batista,&nbsp;Ian A. Wilson,&nbsp;Andrew B. Ward,&nbsp;Rogier W. Sanders","doi":"10.1126/sciimmunol.adk9550","DOIUrl":"10.1126/sciimmunol.adk9550","url":null,"abstract":"<div >Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)–specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100523","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}