ImmunityPub Date : 2025-06-25DOI: 10.1016/j.immuni.2025.05.025
Verena van der Heide, Gabriel Laghlali, Bennett Davenport, Beatrice Cubitt, Vladimir Roudko, Daniel Choo, Kevin Jhun, Etienne Humblin, Abishek Vaidya, Krista Angeliadis, Travis Dawson, Glaucia Furtado, Alice O. Kamphorst, Michael Schotsaert, Rafi Ahmed, Juan Carlos de la Torre, Dirk Homann
{"title":"Prolonged but finite antigen presentation promotes reversible defects of “helpless” memory CD8+ T cells","authors":"Verena van der Heide, Gabriel Laghlali, Bennett Davenport, Beatrice Cubitt, Vladimir Roudko, Daniel Choo, Kevin Jhun, Etienne Humblin, Abishek Vaidya, Krista Angeliadis, Travis Dawson, Glaucia Furtado, Alice O. Kamphorst, Michael Schotsaert, Rafi Ahmed, Juan Carlos de la Torre, Dirk Homann","doi":"10.1016/j.immuni.2025.05.025","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.025","url":null,"abstract":"Generation of functional memory CD8<sup>+</sup> T cells typically requires engagement of CD4<sup>+</sup> T cells. In certain acutely resolving infections, however, effector and memory CD8<sup>+</sup> T (Tmem) cell formation appears impervious to the lack of CD4<sup>+</sup> T cell help. Nevertheless, “helpless” CD8<sup>+</sup> Tmem cells may respond poorly upon rechallenge. The origin and long-term fate of helpless CD8<sup>+</sup> Tmem cells remain incompletely understood. Using multiple host-pathogen systems, we demonstrate that helpless effector CD8<sup>+</sup> T cell differentiation was largely normal, with a paradoxical accumulation of TCF1<sup>hi</sup> “memory precursors.” However, exposure of CD8<sup>+</sup> T cells to residual antigen impaired the development of the Tmem pool. These defects eventually resolved over time, with full restoration of memory potential and recall capacity. Our findings identify prolonged antigen presentation under helpless conditions as an essential determinant for transient CD8<sup>+</sup> Tmem cell dysfunction in acutely resolving infections and highlight plasticity within the Tmem compartment, with implications for vaccination strategies and beyond.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"7 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479514","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 : 2025-06-23DOI: 10.1016/j.immuni.2025.05.026
Leonardo F. Jurado, Andrew W. Daman, Ziyi Li, Vanessa M.S. Ross, Kristina Nikolaou, Kim A. Tran, Oleg Loutochin, Victor A. McPherson, Renaud Prével, Raquel Tarancón, Katalina Couto, Erwan Pernet, Nargis Khan, Jin-Gyu Cheong, Reshma Ramaiah, Mythili Ketavarapu, Eva Kaufmann, Michael S. Glickman, Ajitha Thanabalasuriar, Steven Z. Josefowicz, Maziar Divangahi
{"title":"A fungal-derived adjuvant amplifies the antitumoral potency of Bacillus Calmette-Guérin via reprogramming granulopoiesis","authors":"Leonardo F. Jurado, Andrew W. Daman, Ziyi Li, Vanessa M.S. Ross, Kristina Nikolaou, Kim A. Tran, Oleg Loutochin, Victor A. McPherson, Renaud Prével, Raquel Tarancón, Katalina Couto, Erwan Pernet, Nargis Khan, Jin-Gyu Cheong, Reshma Ramaiah, Mythili Ketavarapu, Eva Kaufmann, Michael S. Glickman, Ajitha Thanabalasuriar, Steven Z. Josefowicz, Maziar Divangahi","doi":"10.1016/j.immuni.2025.05.026","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.026","url":null,"abstract":"In patients with non-muscle invasive bladder cancer, the standard immunotherapy involves intravesical Bacillus Calmette-Guérin (BCG). However, its success requires repeated doses, and ∼50% of patients do not benefit. Using a preclinical orthotopic bladder cancer model, we found that a single intravesical dose of combined BCG and β-glucan immunotherapy eradicated aggressive tumors, resulting in 100% survival. Through single-cell transcriptomic/epigenomic analysis, flow cytometry, and intravital imaging, we show that BCG and β-glucan reprogrammed hematopoietic stem and progenitor cells with imprinting in innate immune cells, particularly neutrophils. Reprogrammed neutrophils exhibited increased reactive oxygen species (ROS) production and infiltration into the tumor core, reducing tumor vascularization and growth. The tumor microenvironment can convert neutrophils into protumor cells; BCG and β-glucan prevented this conversion, promoting sustained antitumoral activity. These findings support β-glucan as a safe, effective adjuvant to enhance BCG immunotherapy in bladder cancer and other solid tumors.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"45 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144341295","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 : 2025-06-23DOI: 10.1016/j.immuni.2025.05.023
Sarah Naguib, Chloe Lopez-Lee, Eileen Ruth Torres, Se-In Lee, Jingjie Zhu, Daphne Zhu, Pearly Ye, Kendra Norman, Mingrui Zhao, Man Ying Wong, Yohannes A. Ambaw, Rodrigo Muñoz-Castañeda, Wei Wang, Tark Patel, Maitreyee Bhagwat, Rada Norinsky, Sue-Ann Mok, Tobias C. Walther, Robert V. Farese, Wenjie Luo, Li Gan
{"title":"The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway","authors":"Sarah Naguib, Chloe Lopez-Lee, Eileen Ruth Torres, Se-In Lee, Jingjie Zhu, Daphne Zhu, Pearly Ye, Kendra Norman, Mingrui Zhao, Man Ying Wong, Yohannes A. Ambaw, Rodrigo Muñoz-Castañeda, Wei Wang, Tark Patel, Maitreyee Bhagwat, Rada Norinsky, Sue-Ann Mok, Tobias C. Walther, Robert V. Farese, Wenjie Luo, Li Gan","doi":"10.1016/j.immuni.2025.05.023","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.023","url":null,"abstract":"The Christchurch mutation (<em>R136S</em>) in the <em>APOE3</em> (<em>E3S/S</em>) gene is associated with attenuated tau load and cognitive decline despite the presence of a causal <em>PSEN1</em> mutation and high amyloid burden in the carrier. However, the molecular mechanisms enabling the <em>E3S/S</em> mutation to mitigate tau-induced neurodegeneration remain unclear. Here, we replaced mouse <em>Apoe</em> with wild-type human <em>APOE3</em> or <em>APOE3S/S</em> on a tauopathy background. The <em>R136S</em> mutation decreased tau load and protected against tau-induced synaptic loss, myelin loss, and reduction in hippocampal theta and gamma power. Additionally, the <em>R136S</em> mutation reduced interferon responses to tau pathology in both mouse and human microglia, suppressing cGAS-STING pathway activation. Treating <em>E3</em> tauopathy mice with a cGAS inhibitor protected against tau-induced synaptic loss and induced transcriptomic alterations similar to the <em>R136S</em> mutation across brain cell types. Thus, suppression of the microglial cGAS-STING-interferon (IFN) pathway plays a central role in mediating the protective effects of <em>R136S</em> against tauopathy.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"51 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144341291","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 : 2025-06-21DOI: 10.1016/j.immuni.2025.05.021
Christopher A. Risley, Michael D. Schultz, S. Rameeza Allie, Shanrun Liu, Jessica N. Peel, Anoma Nellore, Christopher F. Fucile, Christopher D. Scharer, Jeremy M. Boss, Troy D. Randall, Alexander F. Rosenberg, Frances E. Lund
{"title":"Transcription factor T-bet regulates the maintenance and differentiation potential of lymph node and lung effector memory B cell subsets","authors":"Christopher A. Risley, Michael D. Schultz, S. Rameeza Allie, Shanrun Liu, Jessica N. Peel, Anoma Nellore, Christopher F. Fucile, Christopher D. Scharer, Jeremy M. Boss, Troy D. Randall, Alexander F. Rosenberg, Frances E. Lund","doi":"10.1016/j.immuni.2025.05.021","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.021","url":null,"abstract":"While human and mouse memory B cells (MBCs) can express the transcription factor T-bet, its role in regulating MBC function remains unclear. We characterized multiple transcriptionally distinct clusters of mature, somatically mutated nucleoprotein (NP)-specific MBCs in lymph nodes (LNs) and lungs of influenza-infected mice. Although none of the MBCs expressed the plasma cell (PC) lineage commitment factor Blimp1, one cluster was enriched for <em>Tbx21</em><sup>+</sup> cells. Similar to the previously described human T-bet<sup>+</sup> effector MBC (eMBC) population, <em>Tbx21</em><sup>+</sup> mouse MBCs upregulated gene networks associated with effector metabolism, protein synthesis, and the unfolded protein response. Constitutive and inducible ablation of T-bet in murine B cells showed that T-bet expression by MBCs was required for persistence of LN and lung eMBCs with rapid <em>in vitro</em> and <em>in vivo</em> PC differentiation potential. Thus, T-bet marks NP<sup>+</sup> eMBCs that are poised to differentiate, and it regulates maintenance of lung-resident MBCs and local PC responses following virus re-exposure.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"24 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335398","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 : 2025-06-17DOI: 10.1016/j.immuni.2025.05.020
Ananthakrishnan Ganesan, Andrew R. Moore, Hong Zheng, Jiaying Toh, Michael Freedman, Andrew T. Magis, James R. Heath, Purvesh Khatri
{"title":"A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response","authors":"Ananthakrishnan Ganesan, Andrew R. Moore, Hong Zheng, Jiaying Toh, Michael Freedman, Andrew T. Magis, James R. Heath, Purvesh Khatri","doi":"10.1016/j.immuni.2025.05.020","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.020","url":null,"abstract":"Older age, being male, obesity, smoking, and comorbidities (e.g., diabetes, asthma) are associated with an increased risk for severe infections. We hypothesized that there is a conserved common immune dysregulation across these risk factors. We integrated single-cell and bulk transcriptomic data and proteomic data from 12,026 blood samples across 68 cohorts to test this hypothesis. We found that our previously described 42-gene Severe-or-Mild (SoM) signature was associated with each of these risk factors prior to infection. Furthermore, this conserved immune signature was modifiable using immunomodulatory drugs and lifestyle changes. The SoM score predicted the individuals with sepsis who would be harmed by hydrocortisone treatment and individuals with asthma who would not respond to monoclonal antibody treatment. Finally, the SoM score was associated with all-cause mortality. The SoM signature has the potential to redefine the immunologic framing of the baseline immune state and response to chronic, subacute, and acute illnesses.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"23 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305484","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":"Nociceptor-derived CGRP enhances dermal type I conventional dendritic cell function to drive autoreactive CD8+ T cell responses in vitiligo","authors":"Xiuli Yang, Wenxiang Ding, Fangzhou Lou, Hao Xu, Anqi Sheng, Yang Sun, Xiaojie Cai, Miaoni Zhou, Fuquan Lin, Rong Jin, Xichen Zheng, Zhikai Wang, Siyu Deng, Zhenyao Xu, Taiyu Zhang, Jinke Cheng, Xingdong Zheng, Aie Xu, Honglin Wang","doi":"10.1016/j.immuni.2025.05.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.018","url":null,"abstract":"Vitiligo is an autoimmune disease characterized by depigmented patches of skin. Autoreactive CD8<sup>+</sup> T cells kill melanocytes in vitiligo, but the immunopathogenesis remains elusive and ideal drug targets are lacking. Through single-cell and spatial transcriptomic analysis of vitiligo lesional skin, we found that conventional type 1 dendritic cells (cDC1s) primed CD8<sup>+</sup> T cells and highly expressed the neuropeptide calcitonin gene-related peptide (CGRP) receptor. Deletion of Na<sub>v</sub>1.8<sup>+</sup> nociceptors, cDC1-specific ablation of the CGRP receptor, or treatment with a CGRP receptor antagonist (rimegepant) abrogated CD8<sup>+</sup> T cell autoreactivity and prevented skin depigmentation in a mouse model of vitiligo. Conversely, CGRP administration restored vitiligo development in nociceptor-ablated mice. In a pilot study, topical application of rimegepant ointment alleviated skin depigmentation in individuals with vitiligo. Taken together, our results reveal that nociceptor-derived CGRP promotes cDC1-CD8<sup>+</sup> T cell interactions and highlight CGRP receptor antagonism as a potential therapeutic strategy for treating vitiligo.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"44 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296300","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 : 2025-06-16DOI: 10.1016/j.immuni.2025.05.016
Wenqing Zhou, Jordan Z. Zhou, Anees Ahmed, Myeong Joon Kim, Chun-Jun Guo, Gregory F. Sonnenberg
{"title":"ILC3s sense gut microbiota through STING to initiate immune tolerance","authors":"Wenqing Zhou, Jordan Z. Zhou, Anees Ahmed, Myeong Joon Kim, Chun-Jun Guo, Gregory F. Sonnenberg","doi":"10.1016/j.immuni.2025.05.016","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.016","url":null,"abstract":"Immune tolerance to gut microbiota is necessary for health, yet the mechanisms initiating it remain elusive. We profiled MHC II<sup>+</sup> cells at single-cell resolution from the large intestine. Following colonization with the pathobiont <em>Helicobacter hepaticus,</em> group 3 innate lymphoid cells (ILC3s) were a key RORγt<sup>+</sup> antigen-presenting cell that expressed low levels of pattern-recognition receptors but upregulated signatures for antigen presentation and STING signaling. We revealed that STING signaling in ILC3s permitted direct sensing of microbes and enhanced CCR7-dependent migration to gut-draining lymph nodes. ILC3-intrinsic STING signaling supported the instruction of microbiota-specific regulatory T cells and restrained chronic inflammation. However, gut inflammation induced exuberant STING activation, which resulted in the cell death of ILC3s. Our results define STING as a key sensor of gut microbiota in ILC3s. At steady state, this endows ILC3s with the ability to instruct immune tolerance, but heightened STING activation becomes detrimental and eliminates this tissue-protective cell type.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"18 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296298","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":"Structures of butyrophilin multimers reveal a plier-like mechanism for Vγ9Vδ2 T cell receptor activation","authors":"Mai Zhang, Yiqing Wang, Ningning Cai, Yingying Qu, Xianqiang Ma, Jing Xue, Xiaorui Chen, Xueguang Zhang, Junyu Xiao, Yonghui Zhang","doi":"10.1016/j.immuni.2025.05.011","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.011","url":null,"abstract":"Vγ9Vδ2 T cells, the major circulating human γδ T cell subset, respond to infections and tumors by recognizing phosphoantigens (pAgs) via transmembrane butyrophilins (BTN3A1, BTN3A2, and BTN2A1). Here, using cryoelectron microscopy, we resolved the structures of BTN multimers bound to the microbial pAg HMBPP alone and in complex with the T cell receptor (TCR). These structures reveal that BTN3A1 and BTN2A1 cooperate to sense pAgs through their intracellular B30.2 domains, whereas BTN3A2 and BTN2A1 interact extracellularly. TCR engagement triggers its conformational changes, allowing BTN2A1 to bind the Vγ9 chain laterally and BTN3A2 to interact apically with the Vδ2 chain’s germline-encoded regions and CDR3 motif, as well as the Vγ9 CDR3. Our study uncovers a “plier-like gripping” mechanism, where BTN multimers bridge the TCR surface to drive activation. These findings establish a structural foundation for γδ T cell-targeted immunotherapies distinct from αβ T cell strategies reliant on major-histocompatibility-complex-mediated antigen presentation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"9 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260303","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 : 2025-06-10DOI: 10.1016/j.immuni.2025.05.014
Brian Y. Soong, Nader Yatim, Miriam Merad
{"title":"An inside job—CHIP infiltrates and promotes cancer","authors":"Brian Y. Soong, Nader Yatim, Miriam Merad","doi":"10.1016/j.immuni.2025.05.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2025.05.014","url":null,"abstract":"Somatic mutations in hematopoietic stem cells can lead to clonal hematopoiesis of indeterminate potential (CHIP), a frequent condition associated with many age-related diseases including solid cancer. In the <em>New England Journal of Medicine</em>, Pich et al. report that tumor-infiltrating CHIP correlates with worsened cancer prognosis and clinical outcomes, providing evidence for the impact of mutated immune cells on disease progression.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"50 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252437","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}
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