Ji Hyun Sim, Richard Bell, Yurii Chinenov, Zhonghui Feng, Jinyeon Shin, Susan Chyou, William D. Shipman, Yue Xing, Shruti Naik, Niroshana Anandasabapathy, Lionel Ivashkiv, Raghu P. Kataru, Babak Mehrara, Theresa T. Lu
{"title":"Langerhans cell control of early-life dermal lymphatic development shapes adult immunity","authors":"Ji Hyun Sim, Richard Bell, Yurii Chinenov, Zhonghui Feng, Jinyeon Shin, Susan Chyou, William D. Shipman, Yue Xing, Shruti Naik, Niroshana Anandasabapathy, Lionel Ivashkiv, Raghu P. Kataru, Babak Mehrara, Theresa T. Lu","doi":"10.1126/sciimmunol.aed8745","DOIUrl":"10.1126/sciimmunol.aed8745","url":null,"abstract":"<div >The communication between skin and draining lymph nodes is crucial for immune responses to skin insults. Lymphatic vessels play key roles in this communication by transporting antigens from skin to lymph nodes, and mechanisms that compromise dermal lymphatic function can disrupt skin immunity. Here, we show that Langerhans cells (LCs), epidermis-derived antigen-presenting cells, promote dermal lymphatic expansion and phenotype acquisition during early life. This function was mediated by PlGF (placental growth factor) and VEGF-C (vascular endothelial growth factor C), and LCs selectively shaped the transcriptional profile of lymphatic endothelial cells. Compromise of this early-life LC-mediated lymphatic expansion reduced soluble antigen flow to draining lymph nodes and T cell responses in adulthood. Our data identify a tissue-based mechanism by which LCs regulate T cells remotely across time and space and raise the possibility that immune diseases in adulthood could reflect compromise of the LC-lymphatic axis in childhood.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 120","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321719","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":"Erratum for the Research Article “Claudins interact with LILRB immune inhibitory receptors to promote myeloid immunosuppression in cancer”","authors":"","doi":"10.1126/sciimmunol.aej3848","DOIUrl":"10.1126/sciimmunol.aej3848","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 120","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148325059","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}
Zoe C. Schmiechen, Eduardo Cruz-Hinojoza, Audrey L. Hilk, Madeline A. Ellefson, Alexander K. Tsai, Olivia M. Dres, Liang-I Kang, Michael J. Geuenich, Jonah Z. Butler, Adam L. Burrack, Brandon M. Larsen, Grant H. Hickok, Ebony A. Miller, Cara-lin Lonetree, Amrit Gaire, Rachana Pandey, Hezkiel A. Nanda, Indrajit Chaudhury, Thomas Corbiere, Thamotharampillai Dileepan, Steven S. Shen, Kieran R. Campbell, David G. DeNardo, Ingunn M. Stromnes
{"title":"Treg cells promote immunotherapy-induced immune evasion by restraining CD4 T cell control of MHC-I–deficient metastatic pancreatic cancer","authors":"Zoe C. Schmiechen, Eduardo Cruz-Hinojoza, Audrey L. Hilk, Madeline A. Ellefson, Alexander K. Tsai, Olivia M. Dres, Liang-I Kang, Michael J. Geuenich, Jonah Z. Butler, Adam L. Burrack, Brandon M. Larsen, Grant H. Hickok, Ebony A. Miller, Cara-lin Lonetree, Amrit Gaire, Rachana Pandey, Hezkiel A. Nanda, Indrajit Chaudhury, Thomas Corbiere, Thamotharampillai Dileepan, Steven S. Shen, Kieran R. Campbell, David G. DeNardo, Ingunn M. Stromnes","doi":"10.1126/sciimmunol.adz4302","DOIUrl":"10.1126/sciimmunol.adz4302","url":null,"abstract":"<div >Mechanisms driving immunotherapy resistance in pancreatic cancer are poorly defined. We demonstrate that programmed death-ligand 1 immune checkpoint blockade promoted immune evasion by epigenetic <i>Tap1</i> (<i>transporter associated with antigen processing 1</i>) silencing, increasing selection of metastatic tumor variants with defective interferon-γ (IFN-γ)–inducible class I major histocompatibility complex (MHC-I) expression. Unleashing CD4 conventional T cells by regulatory T cell (T<sub>reg</sub> cell) depletion, transfer of tumor-reactive CD4 T cells, or anti–CTLA-4 prevented metastasis. Tumor-specific CD4 T cells adopted a TCF-1<sup>+</sup>SLAMF6<sup>+</sup> progenitor state in lymph nodes and differentiated in tumors. Anti–CTLA-4 increased intratumoral accumulation of CD4 T cells with stemness and tissue residency features, reduced metastasis, and induced gene signatures correlated with improved patient outcomes. MHC-I restoration with anti–CTLA-4 prolonged survival in murine models. In patient tumors, T<sub>reg</sub> cells and CD4 T cells colocalized, and abundance correlated with survival. These findings identify targetable mechanisms of immune evasion and metastasis in immunotherapy-resistant cancer.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 120","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148321721","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":"CXCL16-mediated recruitment of γδ T cells to the brain reduces sociability in mice","authors":"Natsumi Takayama, Koyomi Shiraishi, Ako Matsui, Shinya Hatano, Kazuhiko Yamamuro, Kenta Nitahara, Akira Makino, Tatsuya Yokota, Nesta Amagiri, Mahiro Watanabe, Ayame Nagafuchi, Mio Kawazoe, Minami Serino, Yoshihiro Harada, Tomoaki Takao, Kakeru Takenobu, Yasunobu Yoshikai, Kazufumi Kunimura, Manabu Makinodan, Toru Takumi, Minako Ito","doi":"10.1126/sciimmunol.adz8466","DOIUrl":"10.1126/sciimmunol.adz8466","url":null,"abstract":"<div >Autism spectrum disorder (ASD) is a neurodevelopmental disorder shaped by genetic factors such as copy number variations (CNVs) and immunological factors such as maternal infection. However, most studies on the development of genetic ASD have focused on neurological aspects, and the role of immunity in genetic ASD remains unclear. Here, we demonstrate increased γδ T cells in the brains of 15q11-13 duplication (<i>15q dup</i>) mice, which model a common CNV associated with ASD. Elevated CXCL16 in the brains of <i>15q dup</i> mice promoted γδ T cell infiltration, specifically of Vγ6<sup>+</sup> γδ T cells that produce IL-17A. Deletion of Vγ6<sup>+</sup> γδ T cells throughout development or treatment with neutralizing antibodies against Vγ6 or IL-17A increased social behavior in <i>15q dup</i> mice. These findings suggest that immune dysregulation contributes to social behavior deficits in <i>15q dup</i> mice, consistent with observations in maternal immune activation models, and may represent a potential target for interventions for ASD-associated differences in social behavior.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 120","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adz8466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148282776","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}
Vitka Gres, Florens Lohrmann, Vidmantė Fuchs, Jana Neuber, Zohreh Mansoori Moghadam, Anne K. Lösslein, Lance F. P. Bosch, Tiago Figueiral-Martins, Sebastian Baasch, David Obwegs, Gianni Monaco, Julia Henschel, Klaus P. Knobeloch, Marco Prinz, Steffen Jung, Katrin Kierdorf, Sagar, Julia Kolter, Daniel Erny, Philipp Henneke
{"title":"Bacterial infection reshapes monocyte and macrophage ontogeny at the CNS borders","authors":"Vitka Gres, Florens Lohrmann, Vidmantė Fuchs, Jana Neuber, Zohreh Mansoori Moghadam, Anne K. Lösslein, Lance F. P. Bosch, Tiago Figueiral-Martins, Sebastian Baasch, David Obwegs, Gianni Monaco, Julia Henschel, Klaus P. Knobeloch, Marco Prinz, Steffen Jung, Katrin Kierdorf, Sagar, Julia Kolter, Daniel Erny, Philipp Henneke","doi":"10.1126/sciimmunol.aee9584","DOIUrl":"10.1126/sciimmunol.aee9584","url":null,"abstract":"<div >Macrophages in the meninges contribute to immune defense of the central nervous system (CNS), yet their site-specific origin and function remain poorly understood. Using an intravenous model of streptococcal meningoencephalitis in mice, we found bacteria predominantly in the leptomeninges and dura. Nevertheless, monocyte infiltration into the leptomeninges and parenchyma strongly correlated with disease severity. In the dura, infection triggered activation and loss of resident macrophages, followed by rapid engraftment of inflammatory monocytes that transiently replenished the macrophage niche. Under homeostasis, dural monocytes were supplied CCR2 independently from adjacent skull bone marrow. During infection, this local source was insufficient, necessitating recruitment from peripheral bone marrow. Infection further reshaped monocyte ontogeny, increasing monocyte–dendritic cell progenitor–derived monocytes, which expressed higher major histocompatibility complex class II levels and persisted in the brain alongside CD4<sup>+</sup> T cells during resolution. Together, these findings reveal dynamic, compartment-specific remodeling of monocyte recruitment and differentiation across CNS borders during bacterial meningoencephalitis.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 120","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148282774","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}
Sachin H. Bhagchandani, Stephen Ehrenzeller, Ivan S. Pires, Namit Chaudhary, Carmen J. Booth, Dong-il Kwon, Charalampia Koutsioumpa, Christopher A. Baker, Claire Laxton, Keyla Santos Guedes de Sá, Cullen Matthews, Priya Gill, Sarah Li, Anna Olszowka, Andrew Hudak, Suzanne Fischer, Rafael Bayarri-Olmos, William Brenham Hooper, Akiko Iwasaki
{"title":"Bioactive enhanced adjuvant chemokine oligonucleotide nanoparticles (BEACONs) for mucosal vaccination against genital herpes","authors":"Sachin H. Bhagchandani, Stephen Ehrenzeller, Ivan S. Pires, Namit Chaudhary, Carmen J. Booth, Dong-il Kwon, Charalampia Koutsioumpa, Christopher A. Baker, Claire Laxton, Keyla Santos Guedes de Sá, Cullen Matthews, Priya Gill, Sarah Li, Anna Olszowka, Andrew Hudak, Suzanne Fischer, Rafael Bayarri-Olmos, William Brenham Hooper, Akiko Iwasaki","doi":"10.1126/sciimmunol.aea6419","DOIUrl":"10.1126/sciimmunol.aea6419","url":null,"abstract":"<div >Genital herpes, caused by herpes simplex virus 2 (HSV-2), remains a prevalent sexually transmitted infection with no available vaccine. Effective local immunity, mediated in part by tissue-resident memory T cells (T<sub>RM</sub> cells) and luminal antibodies, provides immediate viral control. Here, we developed bioactive enhanced adjuvant chemokine oligonucleotide nanoparticles (BEACONs) formed via electrostatic interactions between CpG oligodeoxynucleotides (CpG ODNs) and the chemokine CXCL9. This adjuvant enhances antigen-presenting cell engagement and innate immune signaling, promotes CD8 T cell recruitment, and reduces local neutrophilic inflammation relative to CpG ODNs. After intramuscular priming with HSV-2 glycoprotein-encoding messenger RNA–lipid nanoparticles, vaginal boosting with cognate recombinant glycoprotein and BEACONs improved protection against HSV-2 by increasing local CD8 T<sub>RM</sub> cell populations and mucosal antibody responses. Vaccine-mediated protection required local delivery of both antigen and adjuvant and was reduced by CD8 T cell or B cell depletion. These findings support engineered mucosal adjuvants for vaccines targeting genital herpes and other sexually transmitted infections.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 120","pages":""},"PeriodicalIF":16.4,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.aea6419","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148282775","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}
Yang Li, Shachi P. Vyas, Peter Draber, Rami Bechara, Sarah L. Gaffen
{"title":"The tissue-specific regulation of immunobiology by IL-17 signaling","authors":"Yang Li, Shachi P. Vyas, Peter Draber, Rami Bechara, Sarah L. Gaffen","doi":"10.1126/sciimmunol.adq6406","DOIUrl":"10.1126/sciimmunol.adq6406","url":null,"abstract":"<div >IL-17 family cytokines are central regulators of tissue immunity. Here, we review recent advances in defining the cell- and tissue-specific activities of IL-17, emphasizing the signaling pathways engaged by IL-17 receptor (IL-17R) complexes and their associated downstream pathways. We highlight the intersecting transcriptional and posttranscriptional mechanisms that determine IL-17–driven responses and that underlie functional diversity across tissues. Last, we discuss emerging roles for IL-17 signaling in immunometabolism, neuroimmune interactions, cancer, and the latest approaches for targeted therapies.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 120","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238334","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}
Larry Ng, Vincent Tano, Priyankaa Pitcheshwar, Wei Liang Gan, Jinghe Xie, Jesslyn Zhou, Kelvin Han Chung Chong, Danielle Huey Ren Chin, Xi Ren, Omer An, Sze Jing Tang, Vanessa Hui En Ng, Jian Han, Haoqing Shen, Yangyang Song, Daryl Jin Tai Tay, Bryan Y. L. Ng, Bin Wu, Dahai Luo, Leilei Chen
{"title":"DDX6 induces immunosuppression in cancer by disrupting structural stability of endogenous double-stranded RNAs","authors":"Larry Ng, Vincent Tano, Priyankaa Pitcheshwar, Wei Liang Gan, Jinghe Xie, Jesslyn Zhou, Kelvin Han Chung Chong, Danielle Huey Ren Chin, Xi Ren, Omer An, Sze Jing Tang, Vanessa Hui En Ng, Jian Han, Haoqing Shen, Yangyang Song, Daryl Jin Tai Tay, Bryan Y. L. Ng, Bin Wu, Dahai Luo, Leilei Chen","doi":"10.1126/sciimmunol.aea6909","DOIUrl":"10.1126/sciimmunol.aea6909","url":null,"abstract":"<div >Cellular double-stranded RNA (dsRNA) can activate immune pathways similar to viral RNA. Adenosine deaminases acting on RNA 1 (ADAR1)–mediated adenosine-to-inosine (A-to-I) RNA editing has long been believed to destabilize endogenous dsRNA, thus preventing immune activation. We identified DEAD-box RNA helicase 6 (DDX6) as a potent editing repressor and an immune protector under normal conditions but as an immunosuppressor in cancer contexts. Through its interaction with ADAR1, DDX6 binds preferentially to cytoplasmic dsRNA, repressing editing of adenosines in A:C mismatches across the transcriptome, disrupting dsRNA structural stability, and suppressing interferon signaling and immune responses. Depleting DDX6 in tumor cells triggers dsRNA accumulation and activates both intrinsic and extrinsic immunity to hinder tumor growth. Our findings broaden our understanding of the paradigm that RNA editing not only destabilizes cellular dsRNAs but also can stabilize them through I-C pairing, a process preferentially suppressed by DDX6, to limit cytosolic dsRNA sensor recognition. Targeting DDX6 and harnessing RNA-associated tumor cell–intrinsic innate immune activation holds promise for cancer immunotherapy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 120","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.aea6909","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238335","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":"Rogue clones: When MS autoimmunity goes viral","authors":"Jan D. Lünemann","doi":"10.1126/sciimmunol.aej1959","DOIUrl":"10.1126/sciimmunol.aej1959","url":null,"abstract":"<div >Expanded CNS CD8<sup>+</sup> T cell clones in MS can recognize EBV antigens, linking antiviral immunity to ongoing CNS pathology.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 120","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148167234","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}
Roi Balaban, Ori Moskowitz, Maiia Levinson, Noam Ofer, Alice Raizman, Gaya Levi Kitron, Eden Aviv, Sandra Camargo, Lihi Goldman, Aviv Leemann, Eden Noachas, Chen Sharon-Yagol, Amir Giladi, Merav Cohen
{"title":"Efferocytosis induces proangiogenic function and chromatin remodeling in tumor-associated macrophages","authors":"Roi Balaban, Ori Moskowitz, Maiia Levinson, Noam Ofer, Alice Raizman, Gaya Levi Kitron, Eden Aviv, Sandra Camargo, Lihi Goldman, Aviv Leemann, Eden Noachas, Chen Sharon-Yagol, Amir Giladi, Merav Cohen","doi":"10.1126/sciimmunol.aed1544","DOIUrl":"10.1126/sciimmunol.aed1544","url":null,"abstract":"<div >Macrophages remove apoptotic cells by efferocytosis during immune surveillance and in the tumor microenvironment (TME). However, the gradual molecular and epigenetic consequences of efferocytosis in single macrophages remain unclear. Here, we introduce Effero-seq, an approach that captures single-cell transcriptomic changes coupled with lysosomal acidification tracked by a pH-sensitive dye (pHrodo), thus enabling the dissection of molecular dynamics over time after engulfment. Using labeled apoptotic cells as cargo, we defined the effero-score, a gene program gradually up-regulated in correlation with pHrodo intensity. In a murine melanoma model, efferocytosis induced a proangiogenic function in macrophages with spatial proximity to vascular niches. Moreover, efferocytosis remodeled chromatin accessibility, leading to an attenuated macrophage response to interferon-γ. In human uveal melanoma, expression of the effero-score was correlated with poor survival. Therefore, Effero-seq sheds light on the molecular reprogramming induced by efferocytosis in the TME, opening previously unknown avenues for understanding macrophage function and developing targeted treatments.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 120","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148167231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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