ImmunityPub Date : 2026-10-16DOI: 10.1016/j.immuni.2026.09.015
Florent Ginhoux, Kevin Mulder, Sebastian Arcila-Barrera, Ido Amit
{"title":"Embracing macrophage complexity for research and translation.","authors":"Florent Ginhoux, Kevin Mulder, Sebastian Arcila-Barrera, Ido Amit","doi":"10.1016/j.immuni.2026.09.015","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.015","url":null,"abstract":"<p><p>Macrophages are among the most versatile differentiated cell types in the body, serving as key regulators of tissue development, homeostasis, inflammation, repair, and immunity. Their functional diversity cannot be captured by fixed subsets, binary activation states, or single-marker definitions. Macrophage identity emerges instead from the integration of developmental origin, tissue niche, epigenetic history, local environmental cues, and disease-associated signals. Advances in single-cell genomics, spatial profiling, epigenomics, in vivo perturbation, and computational modeling now show that this behavior is organized through modular gene programs, so that any given macrophage state is best described as a weighted combination of program activities rather than a discrete label. We argue that embracing this modular architecture matters not only for annotation but for therapy: macrophage-directed interventions will require defining disease-associated states, identifying surface-accessible entry points into them, and rewiring the underlying programs with spatial and temporal precision.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":""},"PeriodicalIF":30.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206921","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 : 2026-10-15DOI: 10.1016/j.immuni.2026.09.022
Ning Yang,Huixia He,Xin Liu
{"title":"Lactate dehydrogenase A-dependent redox control of selective mRNA translation directs monocyte fate commitment","authors":"Ning Yang,Huixia He,Xin Liu","doi":"10.1016/j.immuni.2026.09.022","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.022","url":null,"abstract":"Monocyte-to-macrophage differentiation is a central process that shapes immune responses across diverse contexts, yet how inflammatory cues engage metabolism to instruct monocyte fate commitment remains unclear. Here, using a CRISPR-based metabolic screen combined with monocyte-specific perturbations in bacterial lung infection, we identified lactate dehydrogenase A (LDHA) as a key metabolic regulator of monocyte commitment to the nitric oxide synthase 2 (NOS2)+ macrophage fate in vivo. LDHA-dependent cytosolic nicotinamide adenine dinucleotide (NAD+) regeneration enabled selective hypoxia-inducible factor 1-alpha (HIF1α) translation through its 5′ untranslated region (UTR) and is associated with structural remodeling of this region. HIF1α then functioned as a downstream effector that promoted the NOS2+ macrophage fate. Granulocyte-macrophage colony-stimulating factor (GM-CSF) further acted as an upstream metabolic priming signal that enhanced LDHA-dependent HIF1α regulation and supported this differentiation process. Together, these findings suggest that metabolic redox state regulates monocyte fate commitment through selective mRNA translation coupled to RNA structural remodeling.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"15 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173078","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 : 2026-10-15DOI: 10.1016/j.immuni.2026.09.019
John J. O’Shea,Lindsey A. Criswell
{"title":"Dan Kastner (1951–2026)","authors":"John J. O’Shea,Lindsey A. Criswell","doi":"10.1016/j.immuni.2026.09.019","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.019","url":null,"abstract":"","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"15 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173077","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.2026.09.021
Agne Antanaviciute,Alison Simmons
{"title":"The matrix remembers","authors":"Agne Antanaviciute,Alison Simmons","doi":"10.1016/j.immuni.2026.09.021","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.021","url":null,"abstract":"Inflammation can have lasting effects, but the mechanisms that drive these effects remain unclear. Adir and colleagues1 reveal that intestinal inflammation leaves a durable imprint in the extracellular matrix. This modified matrix redirects stem-cell fate, sustains wound-associated epithelial programs and promotes persistent immune activation, establishing extracellular matrix memory as a mechanism linking resolved injury to chronic inflammatory disease.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"14 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152675","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.2026.09.018
Rylee J. Beam,Douglas S. Prado,Rebecca A. Elsner
{"title":"Regulatory B cells: Induced, inspired, and ready to soothe neuroinflammation","authors":"Rylee J. Beam,Douglas S. Prado,Rebecca A. Elsner","doi":"10.1016/j.immuni.2026.09.018","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.018","url":null,"abstract":"B cells can promote or restrain inflammation, yet harnessing their regulatory functions has been limited by a lack of understanding of how to efficiently induce them. In this issue of Immunity, Manfroi et al. identify chemical compounds that efficiently induce stable IL-10 production in B cells and demonstrate the ability of these regulatory cells to restrain neuroinflammation.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"90 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152673","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.2026.09.014
Lara Labarta-Bajo,Nicola J. Allen
{"title":"Astrocytes go into presenter mode","authors":"Lara Labarta-Bajo,Nicola J. Allen","doi":"10.1016/j.immuni.2026.09.014","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.014","url":null,"abstract":"Astrocytes are glial cells important for neuronal health, but their functions in CNS immunopathology are less understood. In a recent issue of Nature, Lee et al. report that CD40 engagement and proinflammatory cytokines promote lipid droplet accumulation in astrocytes and subsequent antigen presentation, boosting pathogenic CD4+ T cell responses during experimental autoimmune encephalomyelitis.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"9 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152670","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 : 2026-10-13Epub Date: 2026-08-11DOI: 10.1016/j.immuni.2026.07.010
Chien-Sin Chen, Jacob E Gillis, Jonathan A Cohen, Alexandra R Glathar, Yijia Chen, Eric S Weiss, Lindsay M McKendrick, Caitlin O Bacon, Colton J Smith, Nick J Spencer, Isaac M Chiu, Brian M Davis, Tina L Sumpter, Anthony R Cillo, Amanda C Poholek, Daniel H Kaplan
{"title":"The genesis of cutaneous neurogenic inflammation is a multi-step process requiring dendritic cell aggregation.","authors":"Chien-Sin Chen, Jacob E Gillis, Jonathan A Cohen, Alexandra R Glathar, Yijia Chen, Eric S Weiss, Lindsay M McKendrick, Caitlin O Bacon, Colton J Smith, Nick J Spencer, Isaac M Chiu, Brian M Davis, Tina L Sumpter, Anthony R Cillo, Amanda C Poholek, Daniel H Kaplan","doi":"10.1016/j.immuni.2026.07.010","DOIUrl":"10.1016/j.immuni.2026.07.010","url":null,"abstract":"<p><p>Cutaneous inflammation involving neuroimmune interactions can be initiated by both neurons and immune cells, making it complicated to parse the mechanisms of neurogenic inflammation. Optogenetic activation of Trpv1-expressing nociceptors drives type-17 inflammation in the absence of other inflammatory triggers. We found that two rounds of nociceptor activation were required for Il23a expression and maximal expression of Il1b and Il6, key drivers of type-17 inflammation. The first round of nociceptor activation triggered transient type 2 dendritic cell (DC2) aggregation that required substance P-Mrgprb2-dependent mast cell activation and mast cell-derived chemokine CCL2. Spatial transcriptomic analysis revealed that DC aggregation allowed the second nociceptor stimulation to efficiently activate DCs via the neuropeptide calcitonin gene-related peptide α (CGRPα). Thus, early neurogenic inflammation is a two-step process: substance P induces Mrgprb2-dependent mast cell activation and formation of DC aggregates that allow for efficient subsequent CGRPα-mediated DC activation. These data reveal a multi-cell, dynamic mechanism underlying neurogenic inflammation.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2707-2721.e7"},"PeriodicalIF":30.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712193","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":"Group 2 innate lymphoid cells activate myelin-reactive T cells to augment neuroinflammation.","authors":"Huachen Huang, Gaoyu Liu, Yali Han, Yuyang Miao, Zhibao Zhu, Ying Wang, Jianye Wang, Mengxuan Shi, Jinyi Li, Huaijin Yang, Tongxiao Xu, Caiyun Qi, Jinhao Yang, Wenjun Zhang, Zhaoli Han, Bingbing Wang, De-Cai Tian, Ying Fu, Jie Zhou, Qiang Liu","doi":"10.1016/j.immuni.2026.07.011","DOIUrl":"10.1016/j.immuni.2026.07.011","url":null,"abstract":"<p><p>The meninges are a gateway for pathogenic T cells to enter the central nervous system (CNS). They possess a diverse repertoire of immune cells that orchestrate CNS inflammation and autoimmunity, yet the underlying mechanisms are poorly understood. Here, we report that group 2 innate lymphoid cells (ILC2s) accumulated in the dura as experimental autoimmune encephalomyelitis (EAE) progressed. Single-cell RNA sequencing and flow cytometry analyses revealed distinct features of ILC2s, including expression of MHC class II. ILC2s acted as antigen-presenting cells to activate and expand myelin-reactive T cells in an MHC class II-dependent manner. ILC2-mediated expansion of myelin-reactive T cells increased expression of cytokines IFN-γ and IL-17A. Genetic ablation of ILC2s or of H2-Ab1 in ILC2s alleviated neuroinflammation and CNS demyelination during EAE. These findings revealed a role of ILC2s in neuroinflammation via instructing myelin-reactive T cells, implying targeting ILC2s may be an avenue to restrict CNS inflammation and autoimmunity.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2722-2737.e8"},"PeriodicalIF":30.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684396","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 : 2026-10-13Epub Date: 2026-08-28DOI: 10.1016/j.immuni.2026.08.002
Dan Yuan, Sarah Li, Rongyu Zhang, Rachel H Ng, Yapeng Su, Linda Lan, Mahasish Shome, Brett Smith, Pamela Troisch, Jingyi Xie, Jongchan Choi, Rick Edmark, Daniel Chen, Lee Rowen, Amy Nguyen, Rachel Liu, Vanessa Gutierrez, Conor Brennan, Michaela McKasson, Kim Murray, Julie A Wallick, Heather A Algren, Alexandria Duven, Brian Piening, Wendy Thomas, Hao Y Kueh, Andrew T Magis, Jennifer Hadlock, Michael Snyder, Jason D Goldman, James R Heath
{"title":"A distinct effector B cell population drives autoantibody production in SARS-CoV-2 infection.","authors":"Dan Yuan, Sarah Li, Rongyu Zhang, Rachel H Ng, Yapeng Su, Linda Lan, Mahasish Shome, Brett Smith, Pamela Troisch, Jingyi Xie, Jongchan Choi, Rick Edmark, Daniel Chen, Lee Rowen, Amy Nguyen, Rachel Liu, Vanessa Gutierrez, Conor Brennan, Michaela McKasson, Kim Murray, Julie A Wallick, Heather A Algren, Alexandria Duven, Brian Piening, Wendy Thomas, Hao Y Kueh, Andrew T Magis, Jennifer Hadlock, Michael Snyder, Jason D Goldman, James R Heath","doi":"10.1016/j.immuni.2026.08.002","DOIUrl":"10.1016/j.immuni.2026.08.002","url":null,"abstract":"<p><p>Autoantibodies (autoAbs) are linked to mortality and Long COVID, yet their cellular origins remain unclear. We analyzed the INCOV cohort and identified 12 age- and sex-matched participants with varying autoAb abundance and integrated single-cell RNA-seq and ATAC-seq data from B cells, plasma proteomics, proteome-wide autoAb profiling, clinical data, and in vitro assays. AutoAb abundance inversely correlated with neutralizing IgG and declined as infection resolved, paralleling the contraction of atypical memory B cells (AtMs). In vitro, AtMs preferentially differentiated into autoAb-producing antibody-secreting cells upon TLR7/8 stimulation. CD11c<sup>+</sup> AtMs (double-negative 2, DN2s) in autoAb-high individuals exhibited increased TLR7 signaling, oxidative stress, and isotype switching, regulated by transcription factors T-bet and XBP1. Integrated genetic and genomic analyses showed that DN2s had the strongest enrichment for autoimmune trait heritability and inferred regulatory effects of autoimmune risk variants among B cell subsets. These findings identify DN2s as key precursors of autoAb-producing cells during SARS-CoV-2 infection.</p>","PeriodicalId":13269,"journal":{"name":"Immunity","volume":" ","pages":"2824-2841.e8"},"PeriodicalIF":30.6,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13577201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850149","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 : 2026-10-13DOI: 10.1016/j.immuni.2026.09.017
Byron Shue,Sonja M. Best
{"title":"Viral deISGylation holds the key to the metabolic kingdom","authors":"Byron Shue,Sonja M. Best","doi":"10.1016/j.immuni.2026.09.017","DOIUrl":"https://doi.org/10.1016/j.immuni.2026.09.017","url":null,"abstract":"The interferon-induced modification of cellular and viral proteins by ISG15 inhibits viral infection and is reversed by virus-encoded deISGylases, but the broad physiological impacts of this host-pathogen clash remain unclear. In this issue of Immunity, Zhu et al. reveal that ISG15 modification broadly restricts key metabolic pathways that deISGylation relieves to promote viral replication.","PeriodicalId":13269,"journal":{"name":"Immunity","volume":"31 1","pages":""},"PeriodicalIF":32.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152676","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}