Immunological Reviews最新文献

{"title":"Sex Differences in Metabolite–Immune Circuits of Neuroinflammation","authors":"Priyanka Saminathan,&nbsp;Maija Corey,&nbsp;Alicia Gibbons,&nbsp;Mahati Rayadurgam,&nbsp;Neha Reddy,&nbsp;Pavithra Ramesh,&nbsp;Sonia Sharma","doi":"10.1111/imr.70114","DOIUrl":"10.1111/imr.70114","url":null,"abstract":"<p>Sex is a fundamental yet underexplored determinant of human neuroinflammation. Across autoimmune, neurodegenerative, and post-infectious neurological syndromes, males and females exhibit consistent differences in disease vulnerability, progression, and immune tone. While sex hormones and chromosomes strongly shape immune development and function in health and disease, they do not fully explain the magnitude or disease-specific patterns of these disparities, nor do they provide sufficient mechanistic information for developing novel therapeutics. Emerging evidence suggests that sex-defining factors interact with age and environment to shape downstream metabolite–immune circuits, networks in which metabolic enzymes, metabolites, and immune cells tune inflammatory set points. Pathways spanning purine metabolism, glycolytic remodeling, lipid sensing, mitochondrial stress, and nucleic-acid sensing can recalibrate microglial activation thresholds, T-cell cytokine programs, innate type I interferon antiviral responses, and shape overall CNS resilience in a sex-dependent manner. Here, we synthesize mechanistic and human systems-level studies to propose an integrated framework in which sex-biased immunometabolism serves as a mechanistic bridge between biological sex and neuroimmune disease risk, progression, and responses to injury. We highlight key knowledge gaps and discuss how targeting metabolite–immune pathways may enable sex-informed biomarkers and therapeutic strategies in neuroinflammatory disease.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"338 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12971632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147388852","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":"Dissecting Tumor-Associated Tertiary Lymphoid Structure Formation and Maintenance Using Mouse Models","authors":"Clémence Riffard,&nbsp;Zixi Yin,&nbsp;Kelli A. Connolly,&nbsp;Nikhil S. Joshi","doi":"10.1111/imr.70117","DOIUrl":"10.1111/imr.70117","url":null,"abstract":"<div>\u0000 \u0000 <p>The solid tumor microenvironment is a highly complex system shaped by dynamic interactions among immune and non-immune cell populations. The formation and organization of tumor-associated tertiary lymphoid structures (TA-TLS) have been observed in patients and linked to favorable prognosis and improved response to immunotherapy against a variety of cancers. Since then, preclinical mouse models have been extensively used to recapitulate TA-TLS formation, dissect the underlying mechanisms, and define the cellular interactions licensing TLS anti-tumor activity. Importantly, mouse models allow temporal dissection of TA-TLS development and progression, an aspect that is difficult to capture in humans where analyses are typically limited to endpoint surgical material. Although many steps leading to TLS formation mirror secondary lymphoid organogenesis, a lot is left unknown about what initiates TA-TLS formation and how these transient immune hubs can be manipulated therapeutically in cancer. Notably, while the persistence of TA-TLS in the tumor microenvironment provides a prolonged local anti-tumor immune response, it also enables the accumulation of regulatory cell components (regulatory T and B cells), thus making TLS the sites of both promotion and regulation of the ongoing endogenous immune response. The disruption of germinal centers and the progressive disaggregation of TLS following tumor regression and neoantigen clearance is also an important point where TLS differ from lymph nodes. Whether a form of local tissue memory exists following TA-TLS resolution, and whether this memory allows for faster and more efficient response upon tumor rechallenge, remain open questions. Different preclinical tumor models used to address these questions have their own strengths and limitations. These models are empowered by advances in high-dimensional imaging and spatial profiling technologies. The field of TA-TLS is now reaching a turning point, where emerging techniques promise to help shift from mostly descriptive studies toward a more mechanistic and functional understanding of TLS biology in cancer. Here, we review insights gained from mouse models into TA-TLS formation, persistence, and function, and highlight experimental and technological advances shaping future TLS research.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"338 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147371962","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":"Sex Differences in Cancer Immunotherapy—Clinical Evidence and Mechanisms With a Focus on NSCLC","authors":"Eva Krieghoff-Henning,&nbsp;Balagopal Pai,&nbsp;Maike Collienne,&nbsp;Isabel Ben-Batalla,&nbsp;Sonja Loges","doi":"10.1111/imr.70113","DOIUrl":"10.1111/imr.70113","url":null,"abstract":"<p>Accumulating evidence suggests that the immune system shows subtle but relevant differences between men and women. These differences may have an impact on cancer development and TME composition as well as responses to and adverse events elicited by immunotherapies. Several, albeit not all, clinical trials indicate a greater benefit from mono-immunotherapies over chemotherapies for male patients than for female patients, especially in non-small cell lung cancer and melanoma. Vice versa, female patients might benefit more from chemo-immunotherapies. In human as well as animal models, sex differences in cancer microenvironment composition were described, with partially divergent results. Sex-specific factors such as the levels of hormones, in particular testosterone and estrogen, or X- or Y-chromosome associated genes are likely to drive the observed differences, but are often confounded by external influences such as smoking behavior, diet, or UV exposure. Therefore, large clinical and mechanistic knowledge gaps remain regarding the influence of sex on cancer immunotherapies and strategies to optimize response in either sex. More clinical as well as experimental research in this field is required to close these knowledge gaps, and clinical trials should include large enough groups of male and/or female patients to allow robust sex-specific analyses.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"338 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12949348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147315860","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":"Sex-Specific Factors Influencing HIV Infection","authors":"Maria Pujantell,&nbsp;Marcus Altfeld","doi":"10.1111/imr.70109","DOIUrl":"10.1111/imr.70109","url":null,"abstract":"<p>Immune responses are key in controlling viral infections such as HIV-1, which remains a global challenge to public health. X/Y-chromosome-encoded genes and sex steroid hormones can modulate immune cells and drive distinct patterns of gene and protein expression involved in antiviral function, impacting sex-dependent immune responses and altering the balance of specific immune pathways. These sex-specific differences in antiviral immune responses have significant consequences for the outcome of HIV-1 infection. A better understanding of sex differences in HIV-1-specific antiviral immunity is required to implement and develop new strategies for prevention, treatment and ultimately a functional cure against HIV-1. Here we review the impact of X- and Y-encoded genes and the role of sex steroid hormones on modulating antiviral immune responses against HIV-1 and the consequences for disease manifestations in people living with HIV-1.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"338 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224894","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":"Immune Mechanisms of Viral, Autoimmune, and Immune Checkpoint Inhibitor-Associated Myocarditis","authors":"Wonyoung Jo,&nbsp;Vivian Sun,&nbsp;Daniela Čiháková","doi":"10.1111/imr.70111","DOIUrl":"10.1111/imr.70111","url":null,"abstract":"<div>\u0000 \u0000 <p>Myocarditis and inflammatory cardiomyopathy are immune-mediated diseases of the heart with diverse infectious and noninfectious triggers and heterogeneous outcomes. Viral infection remains the main cause of myocarditis. Noninfectious forms include lymphocytic, eosinophilic, giant cell, cardiac sarcoidosis, and immune checkpoint inhibitor-associated myocarditis. Prognosis worsens with left ventricular dysfunction, heart failure, or malignant arrhythmias, yet the determinants of recovery versus progression to dilated cardiomyopathy (DCM) remain uncertain. This review integrates human studies with mechanistic models to map convergent pathways that connect pattern-recognition signaling, antigen presentation, and T- and B-cell responses with monocyte and macrophage networks that drive injury, fibrosis, and electrical instability. Across etiologies, α-myosin heavy chain (α-MyHC) reactive T cells recur as key effectors. We advance a unifying model in which cardiac tissue-resident memory T cells (TRMs) specific for myosin persist in health but ignite disease when tolerance is breached by infection, injury, or checkpoint blockade. We appraise coxsackievirus B3 (CVB3) infection, experimental autoimmune myocarditis (EAM), and checkpoint perturbation systems that capture patient heterogeneity and enable tracking of antigen-specific responses. Building on these insights, we outline priorities for biomarker-guided endotyping, imaging–omics integration, and targeted immunomodulation that limits progression to inflammatory cardiomyopathy while preserving protective tissue immunity and, in ICI settings, antitumor immunity.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"338 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146224863","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":"Sex Differences in Lung Immunity","authors":"Franz Puttur,&nbsp;Clare M. Lloyd","doi":"10.1111/imr.70102","DOIUrl":"10.1111/imr.70102","url":null,"abstract":"<p>Biological sex has a significant impact on how the immune system develops and responds to foreign and self-antigens. Sex differences exist in innate and adaptive immune cells, both at homeostasis and in the context of infection and inflammatory diseases such as asthma, cancer, and autoimmune disorders. Women generate stronger immune responses and are more susceptible to developing autoimmune conditions, while males are more prone to acute viral infections and developing certain cancers. Some immunological differences persist throughout life, while others emerge only after puberty and before reproductive senescence. Additionally, environmental exposures can affect the influence of biological sex in regulating immune function. This is particularly pertinent at mucosal surfaces such as the lungs, where lung immune defenses are constantly exposed to foreign material during respiration. Consequently, environmental factors together with genetics, age and sex hormones play a vital role in governing lung tissue immune responses between the sexes. In this context, we highlight studies that support the need for considering sex as an important biological variable in lung immunological research. This knowledge will provide a benchmark for understanding sex-driven immunological mechanisms that underpin disease development and may inform new avenues targeted for generating sex-specific therapies in lung disease.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"338 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12907607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199677","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 Thymus Regeneration Paradox: The Search for Stemness in an Involuting Organ","authors":"Roberta Ragazzini,&nbsp;Paola Bonfanti","doi":"10.1111/imr.70110","DOIUrl":"10.1111/imr.70110","url":null,"abstract":"<p>The thymus is emerging as a model for studying organ regeneration and stem cell biology. While research has long focused on how antigen-presenting cells shape the T cell repertoire, recent discoveries unveil a far richer cellular landscape that challenges long-held views of thymus structure and function. This review traces the history of early thymic reconstitution assays, the paradigm of clonal stem cells and serial transplantation, assessing evidence for “stemness” within the thymus. A key focus is the paradox that an involuting thymus retains cells able to expand in culture and reconstitute organ function. We differentiate embryonic/fetal thymus development from postnatal homeostasis, emphasizing how the potency of epithelial progenitor/stem cells shifts with age or upon injury. The role of mesenchymal/interstitial cells and the extracellular milieu is considered alongside advances in organ reconstruction. We outline major unsolved questions in the field: thymus regeneration after childhood; the minimal components required to generate functional naïve T cells outside the body; and the potential of next-generation humanized mouse models to interrogate immune tolerance and novel immunotherapies. We argue that thymus research is entering a new era, one in which understanding and harnessing thymus regenerative potential could yield transformative advances in both basic science and clinical applications.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"338 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12907622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199638","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":"How Does Biological Sex Impact Mucosal Bacterial Infection? Mucosal Defenses and Bacterial Detection","authors":"Laura Ramirez Finn,&nbsp;Molly A. Ingersoll","doi":"10.1111/imr.70112","DOIUrl":"10.1111/imr.70112","url":null,"abstract":"<p>Urinary tract infections possess substantial sex disparities in the incidence, immune response, and progression of infection. Some of these distinctions may be due to sexual dimorphism in mucosal barriers or sex differences in the initial immune response to infection. Mucosal organs are protected by a mucus barrier, however, there is little knowledge of the impact of biological sex on this layer in homeostasis and infection. Notably, despite the incidence of infection, there is a paucity of even fundamental research on bladder mucus in homeostasis and infectious disease. When bacteria encounter mucosal epithelia, they must bind and potentially invade these surfaces to initiate an infection. Whether differences in mucosal epithelia have an impact on bacterial-epithelial interactions between the sexes is not known. When bacteria are sensed by the host, they initiate transcription factor activation, which may differ by sex of the host. Finally, sex steroid hormone receptor signaling likely also impacts innate immunity between the sexes, leading to the divergence between the sexes observed in mucosa infection.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"338 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12906789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197211","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":"Inflammation and Immunogenetics in Cardiomyopathies: From Molecular Mechanisms to Therapeutic Perspectives","authors":"Giovanni Peretto,&nbsp;Andrea Villatore,&nbsp;Leslie T. Cooper Jr.","doi":"10.1111/imr.70105","DOIUrl":"10.1111/imr.70105","url":null,"abstract":"<div>\u0000 \u0000 <p>Genetic variants that impair cardiac function or predispose individuals to autoimmune diseases can influence both the risk and severity of inflammatory heart diseases, including lymphocytic myocarditis and cardiac sarcoidosis. We review recent clinical and experimental studies that describe the emerging interplay between genetic susceptibility and active myocardial inflammation. We summarize the current perspective on the mechanisms of inflammatory pathways and gene-immune interactions, and explore the emerging therapeutic approaches aimed at targeting inflammation in genetic cardiomyopathies.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"338 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099653","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":"Sex Differences in Response to Viral Vector Vaccines—Implications for Future Vaccine Design","authors":"Ilka Grewe,&nbsp;Tamara Zoran,&nbsp;Marylyn Martina Addo","doi":"10.1111/imr.70098","DOIUrl":"10.1111/imr.70098","url":null,"abstract":"<p>Vaccination represents one of the most impactful public health achievements, preventing 3.5 to 5 million deaths annually according to estimates of the World Health Organization. Yet, recent outbreaks of emerging and reemerging infectious diseases highlight the need for rapid and strategic vaccine development using vaccine platforms technologies. Sexual dimorphism in vaccine-induced immune responses has received significant attention in recent years. To ensure vaccine safety and efficacy across sexes, sex-based differences should be considered in vaccine design, dosing, and regimen. Evidence on many traditional vaccines, such as the inactivated influenza vaccine, shows a female bias in innate and adaptive immune responses following vaccination. Thus, it has long been suggested that females universally develop stronger humoral and cellular immune responses to vaccines compared to males. However, compared to traditional vaccines, studies investigating sex differences following vaccination with next-generation platforms, such as viral vector vaccines, remain limited. This review provides an overview of clinical observations of sex differences in responses to replication-competent and replication-deficient, recombinant and nonrecombinant viral vaccines. Additionally, we describe the current state of knowledge on mechanisms of sex-based differences in immune responses and possible implications for future vaccine design.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"338 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12856389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083496","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}