Immunological Reviews最新文献

{"title":"Some Exposure for Influenza Hemagglutinin Interface Antibodies","authors":"Kevin R. McCarthy","doi":"10.1111/imr.70167","DOIUrl":"https://doi.org/10.1111/imr.70167","url":null,"abstract":"<p>Influenza viruses are a constant threat to human health. Current vaccines often confer low to moderate protection against infection with seasonal viruses and little-to-no protection against pandemic viruses. Improved vaccines are needed. These vaccines will need to reliably elicit antibodies to conserved sites that are broadly protective. One strategy to do so is to design immunogens that present epitopes that are targeted by antibodies that are genetically similar, that humans have the genetic capacity to produce, and that are likely present in human naive B cell repertoires. Among the more recently described epitopes for broadly binding, protective antibodies are those on surfaces at protein–protein interfaces. This review will focus on describing many of these sites and the genetic features of antibodies that engage them. Interface epitopes are immunogenic, and antibodies to these sites are likely present in human repertoires following influenza infection or vaccination.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"342 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70167","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interferon-Mediated Regulation of Memory B Cell Identity and Function","authors":"Alana Kirn,&nbsp;Kim L. Good-Jacobson","doi":"10.1111/imr.70161","DOIUrl":"https://doi.org/10.1111/imr.70161","url":null,"abstract":"<p>Memory B cells are essential for long-lasting immunity induced by both encountered pathogens and vaccines. Functional diversity within the memory B cell pool is established through interactions between memory B cells and the environment in which they develop and reside. This review will discuss novel insights into the role of cytokines encountered in the microenvironment in modulating memory B cell transcriptomic, epigenetic, and phenotypic identity. Specifically, it will focus on how interferons can prime unique memory B cell subpopulations upregulated in chronic viral infection, autoimmunity, and cancer. Understanding how memory B cell identity is established and maintained in interferon-primed memory B cell subsets, and how memory B cell phenotype relates to function, may help advise novel vaccine design and diagnostic procedures for a wide range of immunopathologies.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70161","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of the T Cell Receptor Sequence in Shaping T Cell Functional Fate","authors":"Sreekar Mantena,&nbsp;Soumya Raychaudhuri","doi":"10.1111/imr.70157","DOIUrl":"https://doi.org/10.1111/imr.70157","url":null,"abstract":"<div>\u0000 \u0000 <p>The T cell receptor (TCR) has long been studied through the lens of antigen recognition, with decades of work characterizing how the TCR sequence specifies the peptide–MHC ligands a T cell can engage. Yet a growing body of evidence indicates that the TCR sequence carries another dimension of functional information: it biases the transcriptional fate a T cell is likely to adopt. In this review, we synthesize the evidence that TCR sequence features shape T cell differentiation during both thymic development and peripheral responses. We provide an overview of the landscape of T cell fates and the TCR structure, describe advancements in technologies to profile T cell phenotype and TCR sequence, and outline computational strategies for modeling the relationship between them. We specifically examine four reproducible axes of covariation between TCR sequence and T cell fate, including innate-like lineages, regulatory T cells, CD4 versus CD8 commitment, and peripheral memory formation. Understanding the probabilistic fate biases encoded by the TCR may advance our ability to interpret repertoires in health and disease and engineer next-generation cellular therapies.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardio-Immunology: Reframing the Pathogenesis of Cardiovascular Disease","authors":"Douglas L. Mann","doi":"10.1111/imr.70163","DOIUrl":"https://doi.org/10.1111/imr.70163","url":null,"abstract":"&lt;p&gt;For decades, cardiovascular disease was understood primarily through metabolic, hemodynamic, and structural models that linked hypercholesterolemia and hypertension to vascular disease, atherosclerotic plaque formation, ischemic injury, cardiac hypertrophy, and ultimately to the development of heart failure. Over the past 15 years, our understanding of cardiovascular disease pathogenesis has undergone a major conceptual shift, with dysregulated innate and adaptive immune responses now recognized as central features of major cardiovascular disorders, including atherosclerotic coronary artery disease, vascular disease, hypertension, and heart failure (Figure 1). The Cardio-Immunology compendium in this issue of &lt;i&gt;Immunological Reviews&lt;/i&gt; brings together sixteen comprehensive reviews, written by experts and pioneers in their fields that collectively map the immune mechanisms that maintain cardiovascular homeostasis and drive cardiovascular disease, laying the groundwork for precision immune-targeted therapeutics that have the potential to transform cardiovascular care.&lt;/p&gt;&lt;p&gt;A deeper understanding of the role of inflammation in the heart begins with its evolutionary role in preserving tissue homeostasis. In the opening contribution, Mann reframes the relationship between phylogenetically ancient immune responses and myocardial injury through the lens of disease tolerance: A cell-autonomous stress-response program that coordinates cytoprotective signaling in cardiac myocytes with tightly regulated, self-limited inflammatory responses after tissue injury, mediated in part by trained innate immunity [&lt;span&gt;1&lt;/span&gt;]. A central insight highlighted in this article, and a recurrent theme throughout the compendium, is that inflammation is not inherently pathological; rather, its salutary effects become maladaptive when inflammatory responses are dysregulated, excessive, or sustained.&lt;/p&gt;&lt;p&gt;Aging has long been recognized as the strongest risk factor for developing cardiovascular disease; however, therapies that directly target cardiovascular aging remain limited. Zanders, Dimmeler, and colleagues synthesize evidence implicating cellular senescence and the senescence-associated secretory phenotype (SASP) as drivers of inflammaging, chronic low-grade inflammation coupled to vascular and cardiac remodeling [&lt;span&gt;2&lt;/span&gt;]. Senescent cells accumulate in aging cardiovascular tissue, secrete pro-inflammatory mediators, including IL-6, IL-8, TNF, and MMP-3, activate immune cells, and impair tissue repair. Senolytics, SASP modulators, anti-inflammatory agents, and metabolic interventions such as metformin show promise, but translating senescence biology into therapies that improve cardiovascular outcomes in older adults remains an unmet need. Studying immune niches within the myocardium offers another framework for understanding aging-related cardiac dysfunction. Perez-Shibayana, Ludewig, and colleagues describe how immune cells cooperate with fibroblast and ","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70163","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What Does the Shape Space of T Cell Epitopes Look Like?","authors":"Franka Buytenhuijs,&nbsp;Gijs Schröder,&nbsp;Johannes Textor","doi":"10.1111/imr.70152","DOIUrl":"10.1111/imr.70152","url":null,"abstract":"<p><i>Shape space</i> is a decades-old conceptual model of antibody–antigen interactions that underlies antigenic maps used to trace viral evolution. Here, we apply this concept to T cell receptors (TCRs) and the peptide–MHC complexes (pMHCs) that they recognize. We start by reviewing the history of shape space and its deep connections to concepts in statistical physics (energy landscapes) and computer science (complexity theory). Leveraging these connections, we propose a model in which TCR-pMHC binding relies on multiple, possibly conflicting, structural constraints—implying that pMHCs recognized by the same TCR occupy several disjoint, non-convex regions in shape space. Our model makes two central predictions: (1) even small pMHC structure alterations can have major effects on immunogenicity; (2) two pMHCs recognized by the same TCR can have very different structures. We show that published TCR-pMHC interaction data generated by mutagenesis assays lend some support for this idea. We conclude by discussing implications of a multispecific and non-convex T cell epitope shape space for the prediction of immune responses in cancer immunotherapy and other applications.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148682844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative Post-Translational Modifications of Insulin in Type 1 Diabetes Autoimmunity","authors":"Chiara Vinci,&nbsp;Valentina Franzese,&nbsp;Nelig Legoux,&nbsp;Flavia Tramontana,&nbsp;Faheem Shaik,&nbsp;Greta Massa,&nbsp;Paolo Pozzilli,&nbsp;Johnny Ludvigsson,&nbsp;Ahuva Nissim,&nbsp;Rocky Strollo","doi":"10.1111/imr.70159","DOIUrl":"10.1111/imr.70159","url":null,"abstract":"<div>\u0000 \u0000 <p>Type 1 diabetes (T1D) is characterized by T cell-mediated destruction of insulin producing pancreatic β cells. However, stressed β cells are increasingly recognized as active contributors to disease pathogenesis rather than passive targets of immune attack. In this context, oxidative stress in β cells may promote oxidative post-translational modifications (oxPTMs) of insulin, generating modified insulin forms that have emerged as potential drivers of neoantigen formation and autoimmune responses. Due to their exceptionally high insulin biosynthetic load, limited antioxidant defenses, and susceptibility to endoplasmic reticulum and mitochondrial stress, β cells operate in an environment permissive to oxidative protein modification. Multiple studies have demonstrated that insulin is susceptible to several oxidative and nonenzymatic modifications, including oxidation, chlorination, nitration, and glycation, generating structurally distinct proteoforms with altered biological and immunological properties. Importantly, oxidatively modified insulin species (oxPTM-insulin) are recognized by both autoantibodies and autoreactive T cells in individuals with T1D, supporting their role as neoantigens. In this review, we discuss the mechanisms leading to oxPTM-insulin generation, summarize the biochemical and immunological evidence supporting their relevance in T1D, and examine the methodological challenges and controversies surrounding their identification. Finally, we explore the potential of oxPTM-insulin as a biomarker and therapeutic target in T1D.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148682886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-Associated B Cells: Origins, Regulation, and Tissue-Specific Pathogenic Contributions in Autoimmune, Metabolic, and Neurological Diseases","authors":"Kira Rubtsova","doi":"10.1111/imr.70144","DOIUrl":"10.1111/imr.70144","url":null,"abstract":"<p>Age-associated B cells (ABCs) are a distinct B cell population characterized by coexpression of T-bet and CD11c. First described in aged female mice and autoimmune-prone strains, ABCs are now recognized to be associated with multiple human autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, where their frequency correlates with disease activity. Their differentiation requires toll-like receptor (TLR) signaling, IFN-γ, IL-21, BCR engagement, with ZEB2 emerging as the nonredundant transcriptional master regulator of ABC identity. Here we review requirements for ABC differentiation, their defining phenotypic and functional features, and their tissue-specific distribution and pathogenic contributions in diverse inflammatory settings. A central theme is that ABCs are tissue-homing cells whose contribution extends beyond blood and lymphoid organs. In kidney, inflamed synovium, salivary glands, and adipose tissue, ABCs drive pathology through locally differentiated autoantibody-secreting cells, stromal activation, antigen presentation, and cytokine production. We further discuss roles for ABCs in neurological diseases, including their enrichment in the cerebrospinal fluid in multiple sclerosis (MS) and their contribution to neuroinflammation in Alzheimer's disease, and highlight the EBV–ABC axis as a mechanism linking viral infection to autoimmunity. In summary, ABCs are multi-functional, tissue-adaptable pathogenic effectors whose contributions to human disease extend beyond classical autoimmunity into metabolic dysfunction and neurodegeneration.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13443512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Citrullination and Deamidation in Type 1 Diabetes: Linking Beta Cell Stress to Neoantigen-Driven Autoimmunity","authors":"Aïsha Callebaut,&nbsp;Ylke Bruggeman,&nbsp;Chantal Mathieu,&nbsp;Eddie A. James,&nbsp;Lut Overbergh","doi":"10.1111/imr.70158","DOIUrl":"10.1111/imr.70158","url":null,"abstract":"<p>Citrullination and deamidation are post-translational modifications (PTMs) increasingly recognized as important contributors to neoepitope formation in type 1 diabetes (T1D). Under inflammatory and endoplasmic reticulum stress conditions, beta cells activate calcium-dependent peptidylarginine deiminase and transglutaminase enzymes, leading to self-protein modification, altered peptide charge and HLA-binding properties, thereby generating neoepitopes that can be recognized by autoreactive CD4⁺ and CD8⁺ T cells. Accumulating evidence from both murine and human studies demonstrates that immune responses against citrullinated and deamidated beta cell proteins are present and increase with disease progression, supporting a role in epitope spreading rather than disease initiation. Although both PTMs are biochemically analogous, their kinetics and regulation are distinct: citrullination appears as an earlier and partly intrinsic response of stressed beta cells, whereas deamidation is more closely associated with sustained inflammation and later disease stages. In parallel, reduced PTM-generating enzyme expression in the thymus may limit central tolerance to modified epitopes, facilitating escape of autoreactive T cells. In this review, we summarize current insights into the biochemical and immunological roles of citrullination and deamidation in T1D, with emphasis on their temporal regulation, contribution to neoepitope formation, and potential as therapeutic targets, highlighting key findings from our own work in the field.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13443407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The TG2/LRP1 Pathway for T Cell Activation by Post-Translationally Modified Antigens","authors":"Agnele Sylvia Sewa,&nbsp;Fu-Chen Yang,&nbsp;Chaitan Khosla","doi":"10.1111/imr.70155","DOIUrl":"10.1111/imr.70155","url":null,"abstract":"<p>Post-translational modifications (PTMs) can generate neo-epitopes, modified peptides that evade immune tolerance and trigger immune responses. This review focuses on the TG2/LRP1 pathway as a new paradigm for coupling the formation of post-translationally modified peptides with their effective presentation as T-cell antigens by dendritic cells. Transglutaminase 2 (TG2) catalyzes the Gln → Glu conversion of specific residues in peptides derived from dietary gluten thereby enhancing their affinity for HLA-DQ2, the principal genetic determinant of celiac disease. However, because such modified peptides are scarce in intestinal mucosa, an effective mechanism for lysosomal uptake by antigen-presenting cells (APCs) is necessary. Protein–protein interaction between certain peptide-bound TG2 complexes and the low-density lipoprotein receptor-related protein 1 (LRP1) results in efficient endocytosis of these antigenic peptides along with their concomitant release in the endo-lysosomal compartment as deamidated products. An analogous PTM-driven mechanism for antigen presentation may also operate in autoimmune conditions associated with peptidylarginine deiminase (PADI) activity, such as rheumatoid arthritis (RA). The exquisite cellular selectivity of the TG2/LRP1 pathway has implications not only for understanding its role in autoimmunity but also for its potential exploitation in vaccine design.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13437925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148672855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Structure of Vertebrate Antigen Receptor Repertoires: An Evolutionary Perspective","authors":"Thomas Boehm,&nbsp;Orlando B. Giorgetti","doi":"10.1111/imr.70154","DOIUrl":"10.1111/imr.70154","url":null,"abstract":"<p>In vertebrate adaptive immune systems, somatically diversified antigen receptors assume a central role in self/nonself discrimination. Attesting to the presence of a unique but unknown selective environment at early stages of vertebrate evolution, this facility emerged twice, in the ancestors of jawless and jawed vertebrates. Thus, the molecular structure of incomplete antigen receptor genes and their mode of assembly into functional genes are different in the two sister groups of vertebrates. It appears that adaptive immunity evolved in steps, trading immunologically favorable diversity of antigen receptor repertoires against the inherent risks of potentially destructive self recognition. Initially, the associated quality control mechanisms were largely cell-autonomous and grounded in the evolutionarily selected sequence composition of individual components available for assembly. At later stages, diversity increased in lock-step with emerging cell-nonautonomous quality control strategies: primary lymphoid organs spatially and temporally coupled repertoire development and assessment for self reactivity; regulatory cell types emerged to keep self reactive clones in check in the periphery. In this review, we discuss how comparative studies of vertebrate species situated at key positions in the phylogenetic tree have revealed traces of the evolutionary past of adaptive immune systems.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13433984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148667844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}