Immunological Reviews最新文献

{"title":"Machine Learning of Personal Repertoires From Public T Cell Receptors","authors":"Or Malca,&nbsp;Alona Zilberberg,&nbsp;Sol Efroni","doi":"10.1111/imr.70145","DOIUrl":"10.1111/imr.70145","url":null,"abstract":"<p>The T-cell receptor (TCR) repertoire records an individual's immunological history, but most unique CDR3 sequences in any one person are private and uninformative about anyone else. A small subset, however, recurs predictably across unrelated donors. These public TCRβ sequences are independently generated by multiple mechanisms: enrichment by thymic positive selection on a largely shared self-peptide–MHC ligandome, further amplified by selection on common foreign antigens and convergent recombination, together, they are what makes a personal repertoire computationally legible: they provide the shared coordinate system on which otherwise incommensurable repertoires can be aligned and compared. This review takes public TCR sequences as its protagonist. We trace the biology of TCR publicity through new measurements on a 1.5-billion-sequence meta-repertoire (7943 samples, 41 studies) that quantify five interrelated properties: the universe is finite, with Chao2-bounded ceilings (i.e., a lower estimate) of ≈1.97 × 10⁹ amino acid and ≈8.25 × 10⁹ nucleotide CDR3β sequences of which ≈22.5% and ≈12% have already been observed; the rarefaction curve already bends within [0, 7943] by a factor of ×3.3 (amino acid) and ×1.6 (nucleotide) relative to a linear-at-initial-rate extrapolation; publicness is a cohort-scale statistic, with the heavy tail of the publicness distribution growing predictably from <i>N</i> = 200 to <i>N</i> = 7943; super-public sequences are ≈0.014% of unique amino acid CDR3s but carry 8.45% of the total observation mass; and the recapture rate of a CDR3 already observed in another donor reaches 73.3% (amino acid) and 36.2% (nucleotide) at <i>N</i> ≈ 7900. We then trace the family of computational methods that exploit public sequences as features: frequency vectors, sequence-similarity networks, self-supervised transformer embeddings (CVC, Beaker, TCR-BERT, SCEPTR), and our own anchor-based graph neural networks (GraffiTee). We summarize their performance across cancer detection, autoimmunity, infectious disease, immunotherapy monitoring, and immunological aging, alongside the structural confounders (HLA, age, sex, sequencing platform) that bound generalizability. We connect repertoire-level classification to TCR–pMHC binding prediction and antigen identity, and ask what stands between current capabilities and a universal TCR-based diagnostic.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13402767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589777","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 Dual Role of Preexisting Immunity in Influenza: Protective Recall Versus Constraint of Novel Responses","authors":"Annette Fox,&nbsp;Ziheng Zhu,&nbsp;Stephany Sánchez-Ovando","doi":"10.1111/imr.70146","DOIUrl":"10.1111/imr.70146","url":null,"abstract":"<p>Preexisting immunity to influenza confers rapid protection against antigenically matched viruses but can also constrain responses to drifted variants. This review asks when and why prior infection or vaccination is protective versus detrimental, and which biological mechanisms—epitope masking by circulating antibody, inhibitory FcγRIIb signaling, and competitive dominance by affinity-matured memory B cells—drive these outcomes. We synthesize human cohort, serological, and vaccine-effectiveness data with mechanistic mouse and fate-mapping studies to explore how vaccine formulation, antigen dose, antigenic distance and T cell help modulate the balance between memory recall and recruitment of naïve B cells. Finally, we outline strategies (higher dose, adjuvants, multivalent display, and considered strain selection) to restore de novo responses against escape epitopes and improve vaccine performance.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13400904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583146","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":"Hybrid Insulin Peptides as Antigens and Tolerogens for Pathogenic T Cells in Autoimmune Diabetes","authors":"Kathryn Haskins,&nbsp;Thomas Delong,&nbsp;James E. DiLisio,&nbsp;Rocky L. Baker","doi":"10.1111/imr.70142","DOIUrl":"https://doi.org/10.1111/imr.70142","url":null,"abstract":"<div>\u0000 \u0000 <p>In this review, we cover the discovery of hybrid insulin peptides (HIPs) as antigens for CD4 T cells involved in pathogenesis and regulation of autoimmune diabetes. HIPs represent a unique posttranslational modification in autoimmunity and consist of peptide sequences from two beta-cell proteins, one being proinsulin, covalently joined to form new nongenomic peptides. Using the nonobese diabetic (NOD) mouse model, we showed that HIPs are target antigens for a panel of diabetogenic CD4 T-cell clones. The prototype clone of this panel is BDC-2.5, and the first HIP identified was the peptide ligand for BDC-2.5, the 2.5HIP, consisting of an insulin C-peptide fragment combined with a natural cleavage product of chromogranin A. T cells with different TCRs, all specific for the 2.5HIP, were shown to be a dominant population among the T cells infiltrating the islets of NOD mice. T cells reactive to HIPs are significantly elevated in the PBMC of newly diagnosed patients with type 1 diabetes (T1D) and in at-risk subjects, an important finding from a clinical standpoint. When coupled to biodegradable nanoparticles (NPs), HIPs can serve as epitopes to induce antigen-specific tolerance. 2.5HIP NPs not only prevent transfer of disease by BDC-2.5 T cells but also prolong islet graft survival in diabetic NOD mice. Investigation of the mechanisms underlying 2.5HIP NP-induced tolerance revealed that protection occurs through an IL-10-dependent process in which regulatory T cells in the graft tissue are increased, limiting dendritic cell licensing and the subsequent terminal differentiation of both CD4 and CD8 islet-specific T cells.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"341 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148553400","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":"Machine Learning for TCR Repertoire Epitope Annotation and Pattern Discovery","authors":"Romi Vandoren,&nbsp;Vincent Van Deuren,&nbsp;Fabio Affaticati,&nbsp;Sofie Gielis,&nbsp;Kris Laukens,&nbsp;Pieter Meysman","doi":"10.1111/imr.70143","DOIUrl":"10.1111/imr.70143","url":null,"abstract":"<p>T cells are central to adaptive immunity, recognizing antigenic peptides, called epitopes, via the T cell receptor (TCR). The immense diversity and cross-reactivity of the TCR repertoire makes direct interpretation of antigen specificity from repertoire sequencing challenging. High-throughput sequencing enables large-scale profiling of TCRs but does not directly reveal their target epitopes, requiring computational approaches to bridge this gap. This review outlines two complementary strategies, bottom-up and top-down approaches, to annotate TCR specificity. Bottom-up methods predict TCR-epitope specificity from curated TCR-epitope databases, identifying recurring patterns through distance-based, feature-based, or deep learning models. While effective for well-characterized epitopes, they are limited by biased training data, absence of negative data, and weak generalization to unseen epitopes. Top-down approaches instead infer antigen-driven responses from repertoire-level signals such as sequence similarity, enrichment, and TCR convergence. These methods enable discovery of disease- or exposure-associated TCR signatures without prior epitope knowledge but are sensitive to technical noise and biological confounding. Both approaches are complementary as bottom-up provides mechanistic specificity, while top-down enables discovery in complex datasets. Their integration, alongside multimodal modeling and improved benchmarking, is key to advancing TCR-epitope annotation and understanding adaptive immune responses.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"340 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13381816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148519640","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":"Atherosclerotic Cardiovascular Disease and Cancer","authors":"Anaïs Amend,&nbsp;Hauke Horstmann,&nbsp;Kory J. Lavine,&nbsp;Chiara Giannarelli,&nbsp;Kathryn J. Moore","doi":"10.1111/imr.70141","DOIUrl":"10.1111/imr.70141","url":null,"abstract":"<p>Atherosclerotic cardiovascular disease (ASCVD) and cancer are increasingly recognized as interconnected diseases linked by shared immune mechanisms rather than merely overlapping risk factors. Common exposures such as smoking, obesity, diabetes, and dyslipidemia, together with aging and clonal hematopoiesis of indeterminate potential (CHIP), establish a chronic inflammatory milieu that drives both pathologies through coordinated reprogramming of myeloid and lymphoid compartments. Within this framework, a forward cardio-oncology axis is increasingly recognized, in which cancer therapies including chemotherapies, radiation, and immune checkpoint inhibitors induce cardiovascular injury, manifesting as cardiomyopathy, accelerated atherosclerosis, and immune-mediated myocarditis. Complementing this, a reverse axis has emerged in which cardiovascular injury states such as myocardial infarction, ischemia, and heart failure actively promote cancer initiation and progression through hematopoietic remodeling, extracellular vesicle-mediated communication, cardiac-derived factors, and immunosuppressive myeloid bias. At the tissue level, immune checkpoint pathways including PD-1, PD-L1, CTLA-4, LAG-3, and TIM-3 form spatially organized regulatory networks within atherosclerotic plaques. Their therapeutic perturbation restores T cell activity but may disrupt local immune homeostasis and promote plaque instability. In parallel, inflammatory cytokines such as IL-1β, IL-6, and TNF-α, often amplified by CHIP-associated clones, provide a mechanistic bridge linking atherogenesis with tumor immune evasion. Together, these observations support a unified view of ASCVD and cancer as immune-driven diseases connected by bidirectional axes of interaction. This review integrates emerging mechanistic and clinical evidence and outlines how immune-based stratification and targeted modulation of inflammation may enable more precise management of patients at the intersection of cardiovascular disease and cancer.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"340 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70141","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429489","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":"Emerging Roles for Metabolism in Myocardial Inflammation During Heart Failure","authors":"Zipporah Erebholo,&nbsp;Anja Karlstaedt","doi":"10.1111/imr.70128","DOIUrl":"10.1111/imr.70128","url":null,"abstract":"<div>\u0000 \u0000 <p>Metabolic alterations are a hallmark of heart failure and differ across stages. The immune system plays a critical role in cardiac repair and injury during heart failure progression. Metabolic interactions between immune cells and cardiomyocytes are critical for influencing cellular states and cell–cell communications. Understanding these molecular intersections is essential to developing targeted therapies that regulate immunometabolism in the heart. In this review, we provide a comprehensive overview of the metabolic links between immune cells and cardiomyocytes during heart failure and discuss potential treatment strategies.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"340 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417179","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":"Myocardial Immune Niches in Homeostasis and Inflammation","authors":"Christian Perez-Shibayama,&nbsp;Nadine Cadosch,&nbsp;Dörthe Schmidt,&nbsp;Andreas J. Flammer,&nbsp;Frank Ruschitzka,&nbsp;Cristina Gil-Cruz,&nbsp;Burkhard Ludewig","doi":"10.1111/imr.70139","DOIUrl":"10.1111/imr.70139","url":null,"abstract":"<p>The heart functions as a circulatory pump that supplies blood throughout the body. The execution of this critical function depends on the interplay between cardiomyocytes and the supportive cellular infrastructure, generated by endothelial cells, fibroblasts and distinct immune cell populations. Immune cells cooperate with fibroblastic and endothelial stromal cells across different cellular ecosystems to maintain tissue integrity and function. In the homeostatic state, immune-stromal interactions in specific niche environments govern critical cardiomyocyte functions such as contractility and metabolic balance. Inflammatory perturbations disrupt the equilibrated cellular interactions leading to local stromal and immune cell activation. Dedicated regulatory mechanisms and circuits direct immune cell functions in the inflamed myocardium to prevent maladaptive remodeling processes, which could manifest as cardiac fibrosis, arrhythmia, or heart failure. Here, we discuss an immune niche-based view on myocardial immunity based on anatomically and functionally distinct niche environments. We summarize recent progress on the key molecular and cellular components and their interactions within cardiac immune niches and highlight immunological mechanisms and pathways that maintain cardiomyocyte integrity and function.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"340 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417154","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":"Modeling TCR-Epitope Recognition Specificity: What We Should Learn to Succeed","authors":"David Gfeller,&nbsp;Julien Racle,&nbsp;Rita Ann Roessner","doi":"10.1111/imr.70140","DOIUrl":"10.1111/imr.70140","url":null,"abstract":"<p>T-cell recognition of infected or malignant cells is central to both spontaneous and therapy-induced cellular immune responses against pathogens and cancer. This recognition is elicited by the interaction between T-Cell Receptors (TCRs) and epitopes, which consist of antigenic peptides displayed on major histocompatibility complex molecules. TCR-epitope interactions are characterized by high diversity in TCR and epitope sequences and high structural flexibility in TCR loops. As a result, deciphering the rules of TCR-epitope recognition specificity and accurately predicting these interactions remains challenging. Here, we review the different strategies developed to predict TCR-epitope recognition, classify the principal computational frameworks, examine the data modalities on which they depend and discuss their current limitations. We then synthesize key conceptual insights that have emerged from recent research and outline how these lessons should inform the design of future experiments and next-generation computational tools.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"340 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70140","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417168","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":"Diversity, Equality, and Inclusion in the naïve T Cell Receptor Repertoire","authors":"Isabella Sodi,&nbsp;Matthew V. Cowley,&nbsp;Trupti Gore,&nbsp;James Henderson,&nbsp;Andreas Tiffeau-Mayer,&nbsp;Benny Chain","doi":"10.1111/imr.70138","DOIUrl":"10.1111/imr.70138","url":null,"abstract":"<p>The naïve T cell receptor (TCR) repertoire forms the immunological background from which adaptive cellular immune responses emerge. We examine the fundamental properties of the human naïve TCR repertoire through the perspective of Diversity, Equality, and Inclusion. We first consider the richness of the repertoire. A combination of experimental and computational approaches has been used to estimate that the human repertoire contains at least 100 million distinct naïve clonotypes. This estimate suggests an average size of each clonotype of 1000 T cells. However, evidence from both mathematical modeling and large-scale single-cell sequencing indicates that clonotype family sizes are very unequal, with a small subset of naïve TCRs present at substantially higher frequencies. Somatic recombination itself does not contribute significantly to this inequality, as the probability of generating an identical clonotype multiple times in an individual is very small. Instead, clonotype size is likely to be largely driven by thymic or post-thymic expansion, but the mechanisms driving heterogeneity remain poorly understood. Finally, despite clonal deletion being a cornerstone of immunological dogma, experimental evidence for functional “holes” in the naïve repertoire caused by negative thymic selection is surprisingly limited. Alternative tolerance mechanisms, including regulatory T cells and T cell quorum sensing, are likely to play important roles. This review highlights the need for further research to identify the mechanisms that shape the frequency distribution of naïve TCR clone sizes and to define its impact on primary immune responses. Further research is also needed to understand the role of quorum sensing in maintaining T cell tolerance, while avoiding potential vulnerabilities arising from extensive ‘holes’ in the TCR repertoire.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"340 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70138","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366206","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":"Macrophage Plasticity and Immune Remodeling in Ischemic Heart Failure","authors":"Claire Xiao,&nbsp;Lucy MacDonald,&nbsp;Slava Epelman,&nbsp;Kory J. Lavine","doi":"10.1111/imr.70137","DOIUrl":"10.1111/imr.70137","url":null,"abstract":"<div>\u0000 \u0000 <p>Macrophages, as central effectors of innate immunity, play context-specific and time-dependent roles in myocardial infarction (MI) and in the pathogenesis of ischemic heart failure (HF). Their plasticity, heterogeneity, and interactions with other cardiac and immune cells determine whether inflammation resolves and repair ensues, or maladaptive remodeling culminates in ventricular dysfunction. In this review, we synthesize findings from lineage-tracing studies, single-cell transcriptomic atlases, and clinical trials to highlight macrophage ontogeny, recruitment, reparative programs, and pathogenic functions in chronic remodeling. We discuss embryonically-derived cardiac resident macrophages, recruitment of monocyte-derived macrophages and their respective roles after ischemic injury, and how efferocytotic clearance of cellular and mitochondrial debris is a key component of the reparative response. We highlight macrophage interactions with cardiomyocytes, fibroblasts, neutrophils, T cells, and conduction system cells, and outline translational strategies involving chemokine pathway inhibition and specialized pro-resolving mediators. Mechanistic insight into macrophage ontogeny, heterogeneity, and intercellular interactions has uncovered novel therapeutic possibilities. Targeted, temporally staged macrophage therapies, using biomarkers and imaging for patient stratification, may improve post-MI healing and prevent progression toward ischemic HF.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"340 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148292841","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}