ImmunityPub Date : 2026-10-13Epub Date: 2026-07-13DOI: 10.1016/j.immuni.2026.06.011
Samuel W Kazer, Jaclyn M L Walsh, Lillian J Juttukonda, Jose Ordovas-Montanes
{"title":"Nasal immunity in respiratory viral infection, transmission, and protection.","authors":"Samuel W Kazer, Jaclyn M L Walsh, Lillian J Juttukonda, Jose Ordovas-Montanes","doi":"10.1016/j.immuni.2026.06.011","DOIUrl":"10.1016/j.immuni.2026.06.011","url":null,"abstract":"<p><p>The nasal mucosa plays key roles in protecting against airborne pathogens as the major barrier to the airway. Catalyzed by the COVID-19 pandemic, recent studies focusing on nasal immunity have begun to elucidate how epithelial and immune cells work in concert to fight viral infection, reduce spread to the lower airways, and limit onward transmission. Technologies such as single-cell RNA sequencing and air-liquid interface models are enabling high-resolution views of the cell states and responses that dictate infection resolution and memory formation. Here, we review our current understanding of the cells of the nasal mucosa at homeostasis and their responses during and following viral infection in mice and humans. We discuss emerging correlates of protection before and after exposure, noting the differences between infection and intramuscular vaccination. Finally, we examine novel intranasal vaccination strategies and propose approaches to program tissue-scale memory into the nose to prevent disease and viral spread.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2623-2642"},"PeriodicalIF":30.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13372208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436459","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}
ImmunityPub Date : 2026-10-13Epub Date: 2026-08-06DOI: 10.1016/j.immuni.2026.07.007
Junji Zhu, GuanQun Liu, Jielin Xu, Zuberwasim Sayyad, Kun Li, Surajit Chakraborty, Christopher M Goins, Huaxu Yu, Yadi Zhou, Shanti Ross, Evangeline White, Jun Zhao, Oliver Fiehn, Shaun R Stauffer, Feixiong Cheng, Michaela U Gack
{"title":"Virus-induced deconjugation of ISG15 dysregulates innate immunity and cellular metabolism.","authors":"Junji Zhu, GuanQun Liu, Jielin Xu, Zuberwasim Sayyad, Kun Li, Surajit Chakraborty, Christopher M Goins, Huaxu Yu, Yadi Zhou, Shanti Ross, Evangeline White, Jun Zhao, Oliver Fiehn, Shaun R Stauffer, Feixiong Cheng, Michaela U Gack","doi":"10.1016/j.immuni.2026.07.007","DOIUrl":"10.1016/j.immuni.2026.07.007","url":null,"abstract":"<p><p>Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that regulates diverse cellular responses, including antiviral immunity, through its conjugation to proteins in a process known as ISGylation. Several pathogens, including SARS-CoV-2, subvert ISGylation by encoding deISGylating enzymes. However, the direct targets and physiological consequences of coronaviral deISGylation remain poorly defined. Here, we genetically ablated the deISGylating activity of the SARS-CoV-2-encoded papain-like protease (PLpro) and found that loss of deISGylation boosted innate immune activation, attenuated viral replication, and promoted viral clearance in human cells and mice. Metabolomics, ISGylome proteomics, and functional analyses revealed that PLpro deISGylation relieved metabolic restriction of virus infection by directly regulating the activity of key enzymes controlling glycolysis, the pentose phosphate pathway, and redox homeostasis. These findings provide fundamental insight into how reversible ISGylation regulates immunity and metabolic processes at the molecular level and highlight viral deISGylation as a major strategy to overcome host immunometabolic defenses.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2654-2670.e13"},"PeriodicalIF":30.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684354","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}
ImmunityPub Date : 2026-10-13DOI: 10.1016/j.immuni.2026.09.016
Jun Yu,Carlos-Filipe Pereira,Liangtao Zheng,Zemin Zhang,Georg Schett,Johann E. Gudjonsson,Kathryn Monroe,Teresa Lambe
{"title":"Multidimensional view of immunotherapy","authors":"Jun Yu,Carlos-Filipe Pereira,Liangtao Zheng,Zemin Zhang,Georg Schett,Johann E. Gudjonsson,Kathryn Monroe,Teresa Lambe","doi":"10.1016/j.immuni.2026.09.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.016","url":null,"abstract":"The introduction of immune checkpoint blockade revolutionized cancer treatments. Since then, the field of immunotherapy has expanded exponentially, both in therapeutic innovations and applicable disease contexts. Investigators across disciplines discuss how they are reimagining strategies to drive the immune system in contexts of cancer, autoimmunity, and beyond.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"78 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152677","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}
ImmunityPub Date : 2026-10-13DOI: 10.1016/j.immuni.2026.09.020
Evan W. Newell
{"title":"The narrow path to CD8+ T cell recognition of mutant p53","authors":"Evan W. Newell","doi":"10.1016/j.immuni.2026.09.020","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.020","url":null,"abstract":"Shared cancer driver mutations offer attractive targets for cancer immunotherapy, but their expression does not necessarily put them within the reach of a T cell response. In this issue of Immunity, Haratani et al. identify distinct barriers to the processing, presentation, and recognition of neoantigens generated from mutant p53 that help explain this gap.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"68 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152671","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}
ImmunityPub Date : 2026-10-13DOI: 10.1016/j.immuni.2026.09.008
Kenji Kabashima
{"title":"The nerve rings twice","authors":"Kenji Kabashima","doi":"10.1016/j.immuni.2026.09.008","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.008","url":null,"abstract":"How does neural activity ignite skin inflammation? In this issue, Chen et al. show that one round of nociceptor activation builds a transient, chemokine CCL2-dependent dendritic cell-rich neighborhood, whereas a second round within the tested 3–12-h range licenses an IL-23-centered program through neuropeptide CGRPα.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"49 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152674","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":"Skin-resident CXCR6+ memory CD4+ T cells and dendritic cells form dermal perivascular hubs that drive relapse in allergic dermatitis","authors":"Ryota Asahina,Fuuka Minami,Satoshi Nakamizo,Toshiya Miyake,Satoru Yonekura,Toshiaki Kogame,Shuto Kanameishi,Kosuke Katsuo,Hiroyuki Irie,Saeko Nakajima,Takashi Nomura,Akihiko Kitoh,Gyohei Egawa,Kenji Kabashima","doi":"10.1016/j.immuni.2026.09.010","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.010","url":null,"abstract":"CD4+ tissue-resident memory T (TRM) cells are crucial for relapse in allergic skin conditions. However, the mechanisms underlying their maintenance and pathogenic potential remain poorly defined. Here, across multiple models of allergic dermatitis, we identified a C-X-C chemokine receptor 6 (CXCR6+) subpopulation within CD4+ TRM cells as a distinct pathogenic subset that rapidly induces relapse. This subset is supported by C-X-C chemokine ligand 16 (CXCL16)-dependent interactions with CD301b+ conventional type 2 dendritic cells (cDC2s) for in situ maintenance. Functional blockade of the CXCL16-CXCR6 signaling pathway impaired proliferation and maintenance of CXCR6+ CD4+ TRM cells. In human atopic dermatitis (AD), CXCR6+ CD4+ TRM cells co-localized with CD301+ cDC2s in perivascular clusters even after successful anti-IL-13 therapy. These findings point to CXCR6+ CD4+ TRM cells as a pathogenic reservoir sustaining chronic and recurrent inflammation and suggest the CXCL16-CXCR6 axis as a therapeutic target to prevent relapse in allergic skin diseases.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"45 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151826","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}
ImmunityPub Date : 2026-10-09DOI: 10.1016/j.immuni.2026.09.012
Marina Terekhova, Maksim Kleverov, Thomas Francis, Dmitrii Usoltsev, Pavla Bohacova, Laura Arthur, Petr Tsurinov, Denis Kleverov, Luke Trinity, Kamila Husarcikova, Ivan Molotkov, Titas Grabauskas, Amir Fathi, Eloise Milbourn, Esme Newton, Leah Siegel, Adnaan Ghanchi, Urika Tse, Ross D Pollock, Niharika A Duggal, Janet M Lord, Norman R Lazarus, Ali H Ellebedy, Duygu Ucar, Stephen D R Harridge, Mykyta Artomov, Maxim N Artyomov
{"title":"Single-cell analyses of global cohorts outline determinants of immune aging and link the ratio of GZMK<sup>+</sup> to GZMB<sup>+</sup> Tem cells to health trajectories.","authors":"Marina Terekhova, Maksim Kleverov, Thomas Francis, Dmitrii Usoltsev, Pavla Bohacova, Laura Arthur, Petr Tsurinov, Denis Kleverov, Luke Trinity, Kamila Husarcikova, Ivan Molotkov, Titas Grabauskas, Amir Fathi, Eloise Milbourn, Esme Newton, Leah Siegel, Adnaan Ghanchi, Urika Tse, Ross D Pollock, Niharika A Duggal, Janet M Lord, Norman R Lazarus, Ali H Ellebedy, Duygu Ucar, Stephen D R Harridge, Mykyta Artomov, Maxim N Artyomov","doi":"10.1016/j.immuni.2026.09.012","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.012","url":null,"abstract":"<p><p>Human immune aging is heterogeneous, with immune responses becoming increasingly variable over the lifespan. Here, we integrated seven large-scale public single-cell peripheral blood mononuclear cell (PBMC) datasets and a newly generated cohort, encompassing 2,609 ostensibly healthy individuals across diverse ages, ancestries, and biological sexes. We identified both conserved and cohort-associated age-associated remodeling across 59 immune populations, together with sex- and ancestry-dependent immune differences. CD8<sup>+</sup> T cells emerged as major drivers of aging heterogeneity, with the GZMK<sup>+</sup>/GZMB<sup>+</sup> effector memory ratio distinguishing healthy and pathology-associated aging trajectories. This ratio reflected immune remodeling driven by chronic viral exposure, including CMV, and disease-associated immune dysregulation, with the dominant driver varying across populations. Proteomic profiling across four cohorts revealed a Tem GZMB<sup>+</sup> plasma signature associated with inflammaging, poor self-reported health, all-cause mortality, and increased risk of immune-related, metabolic, and cardiovascular diseases. Together, these findings define clinically relevant immune determinants for monitoring and guiding healthy aging interventions.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":30.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147683","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}
ImmunityPub Date : 2026-10-09DOI: 10.1016/j.immuni.2026.09.013
Tenny Mudianto, Gabrielle R Berman, Kimberly Zaldana, Marta Schips, Niklas Schwan, Luan Firmino-Cruz, Jana Bilanovic, Ochapa Ibrahim, Vanessa Cristaldi, William S Foster, Lina Fikri, Sabrina Solis, Han Chen, Dimitri Kakabadse-Schmidt, Michael Cammer, Ramin Sedaghat Herati, Sergei B Koralov, Andrew David Miller, Michael Meyer-Hermann, Carla R Nowosad, Amanda W Lund
{"title":"Lymphatic constraint of germinal centers optimizes protective antibody responses.","authors":"Tenny Mudianto, Gabrielle R Berman, Kimberly Zaldana, Marta Schips, Niklas Schwan, Luan Firmino-Cruz, Jana Bilanovic, Ochapa Ibrahim, Vanessa Cristaldi, William S Foster, Lina Fikri, Sabrina Solis, Han Chen, Dimitri Kakabadse-Schmidt, Michael Cammer, Ramin Sedaghat Herati, Sergei B Koralov, Andrew David Miller, Michael Meyer-Hermann, Carla R Nowosad, Amanda W Lund","doi":"10.1016/j.immuni.2026.09.013","DOIUrl":"10.1016/j.immuni.2026.09.013","url":null,"abstract":"<p><p>Immunization strategies are central to pathogen control, where efficacy relies on antigen distribution and inflammatory context. Lymphatic vessels are necessary conduits for antigen transport that actively remodel in peripheral tissues and draining lymph nodes (LNs) in response to their inflammatory context. In this study, we found that inhibiting viral-induced lymphatic remodeling in skin and LNs prompted germinal center (GC) expansion but, paradoxically, decreased the protective antibody response. While GCs scaled proportionately, larger GCs failed to support proliferative bursts consistent with clonal selection due to impaired T-B cell interactions. Accordingly, follicle and GC size are evolutionarily conserved across diverse mammals despite increased LN size. Lymphatic vessels controlled GC size through two coordinated processes: lymphatic remodeling in infected skin limited viral transport to the LN, while the resulting permissive environment in the LN supported perifollicular lymphangiogenesis that constrained GC expansion.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":30.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148687","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}
ImmunityPub Date : 2026-10-08DOI: 10.1016/j.immuni.2026.09.011
Evi Paouri,Sarah Stanko,Nadia Gasmi,Gabriele Glusauskas,Valery Mao,Andrew Kwak,Stephanie Hsu,Sahar Sarmadi,Emily Huang,Aniruddha Das,Courtney Hershberger,Quinn Watercutter,Megan R. McMullen,Christopher Birck,Hope Burton,Hale Tobin,Anxhela Gjojdeshi,Julia Dziabis,Richa M. Hanamsagar,Daniel M. Rotroff,Richard A. Prayson,Staci D. Bilbo,Saba Valadkhan,Hod Dana,Laura E. Nagy,Dimitrios Davalos
{"title":"Microglia-mediated extracellular matrix disruption drives neuronal dysfunction, motor impairments, and sedation following alcohol abuse","authors":"Evi Paouri,Sarah Stanko,Nadia Gasmi,Gabriele Glusauskas,Valery Mao,Andrew Kwak,Stephanie Hsu,Sahar Sarmadi,Emily Huang,Aniruddha Das,Courtney Hershberger,Quinn Watercutter,Megan R. McMullen,Christopher Birck,Hope Burton,Hale Tobin,Anxhela Gjojdeshi,Julia Dziabis,Richa M. Hanamsagar,Daniel M. Rotroff,Richard A. Prayson,Staci D. Bilbo,Saba Valadkhan,Hod Dana,Laura E. Nagy,Dimitrios Davalos","doi":"10.1016/j.immuni.2026.09.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.011","url":null,"abstract":"Alcohol abuse is the primary risk factor for alcohol use disorder (AUD), a leading cause of preventable morbidity and mortality worldwide. While direct effects of alcohol on neuronal function are well established, the role of microglia in acute and chronic neurological dysfunction in AUD remains underappreciated. Using mouse models of binge and high-intensity alcohol exposure and longitudinal in vivo imaging, we found that microglia exhibited acute and progressive morphological responses that preceded but paralleled ethanol-induced sedation. Ethanol also induced microglia-dependent extracellular matrix (ECM) disruption, synapse elimination, and reduced neuronal activity and density. Genetic deletion of microglial Myd88 protected against ethanol-induced microglial reactivity, neuronal damage and dysfunction, intoxication, and motor impairments by preventing ECM disruption. Frontal cortex ECM was similarly disrupted in human brain tissue from individuals with AUD. These findings identify microglia as cellular drivers of brain dysfunction following alcohol abuse and MyD88 as a critical therapeutic target for AUD.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"10 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149124072","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}
ImmunityPub Date : 2026-10-01DOI: 10.1016/j.immuni.2026.09.007
Marius Messemaker,Bjørn P.Y. Kwee,Živa Moravec,Sam de Paauw,Jos Urbanus,Daniel Álvarez-Salmoral,Jeroen Geerligs,Ren Xie,Rhianne Voogd,Ben Morris,Aurélie Guislain,Yaël Winkler,Connor A. Richterich,Maike Mussmann,Marijn Bakker,Maxime Steinmetz,Matyas Iras,Eric Marcus,Jonas Teuwen,Anastassis Perrakis,Roderick L. Beijersbergen,Wouter Scheper,Ton N. Schumacher
{"title":"Functional evaluation of TCR-pMHC pairs at scale allows in silico TCR reactivity prediction","authors":"Marius Messemaker,Bjørn P.Y. Kwee,Živa Moravec,Sam de Paauw,Jos Urbanus,Daniel Álvarez-Salmoral,Jeroen Geerligs,Ren Xie,Rhianne Voogd,Ben Morris,Aurélie Guislain,Yaël Winkler,Connor A. Richterich,Maike Mussmann,Marijn Bakker,Maxime Steinmetz,Matyas Iras,Eric Marcus,Jonas Teuwen,Anastassis Perrakis,Roderick L. Beijersbergen,Wouter Scheper,Ton N. Schumacher","doi":"10.1016/j.immuni.2026.09.007","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.007","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"2 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149090244","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}