Immunological Reviews最新文献

{"title":"An Outside-In View of the Beneficial and Detrimental Impact of Type-2 Inflammation in the Lung","authors":"Richard Lee Reinhardt","doi":"10.1111/imr.70041","DOIUrl":"https://doi.org/10.1111/imr.70041","url":null,"abstract":"<p>Bacterial and viral infections initiate classical type-1 immune responses. Together, pathogen-specific CD8+ cytotoxic T cells, CD4+ T helper 1 (Th1) cells, and classically activated macrophages cooperate to kill and eliminate infected cells. After pathogen clearance, the type-1 response resolves. Resolution of a classical inflammatory response is critical to host health. The importance of limiting inflammation after pathogen clearance is evident from the association of chronic type-1 inflammation with diverse diseases ranging from inflammatory bowel disease, chronic obstructive pulmonary disease, diabetes, and Alzheimer's disease [<span>1-4</span>].</p><p>While optimal for protection against viruses and bacteria, type-1 inflammation is not effective at controlling large extracellular helminths. These worms are orders of magnitude larger than viruses and bacteria, preventing classical macrophage clearance and phagocytosis of infected cells. If such a response was mounted, the inability of the host to clear the worms would lead to persistent type-1 inflammation. As stated above, such persistence of type-1 inflammation would ultimately be detrimental to the host. To avoid this, mammals have evolved the ability to mount a type-2 immune response to combat extracellular worm infections [<span>5, 6</span>]. Unlike type-1-driven immunity, which is focused on the direct killing and clearance of infected cells, type-2 inflammation is centered on the recruitment of innate immune cells to the site of infection; limiting nutrient availability during feeding by walling off the attachment site (wound healing response); and clearing of the worm through mucus production and smooth muscle contraction (weep and sweep). Also important, type-2 inflammation suppresses classical type-1 inflammation. These processes occur in multiple tissues infected by these parasites including the lung.</p><p>However, type-2 inflammation can also be detrimental to the host. If a type-2 response is evoked in the presence of a normally inert protein (allergen), it can be associated with allergic disease. In the context of the lung, type-2 inflammation to allergens is defined as allergic asthma [<span>7</span>]. Interestingly, the pathobiology associated with soil-transmitted helminth infection, as they migrate through the lung, closely resembles the pathobiology seen in the lungs of asthmatics. In both cases, the classical hallmarks of type-2 inflammation are evident: eosinophilia, goblet cell hyperplasia and mucus production, and elevated immunoglobulin-E, IgG1, and IgG4.</p><p>These classical hallmarks of type-2 inflammation are driven in large part by the production of type-2 cytokines—interleukin-4, IL-5, and IL-13 [<span>8</span>]. IL-4 is critical for the class-switching of B cells to IgE and IgG1. IL-5 mobilizes eosinophils from the bone marrow. IL-13 drives both the induction of goblet cell hyperplasia and mucus production as well as smooth muscle contractility. The critical ","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"332 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144292447","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 Immunology of Alpha-Gal Syndrome: History, Tick Bites, IgE, and Delayed Anaphylaxis to Mammalian Meat","authors":"Thomas A. E. Platts-Mills,&nbsp;Roopesh Singh Gangwar,&nbsp;Lisa Workman,&nbsp;Jeffrey M. Wilson","doi":"10.1111/imr.70035","DOIUrl":"https://doi.org/10.1111/imr.70035","url":null,"abstract":"<p>The primary features of the alpha-gal syndrome (AGS) are (i) The IgE ab that are causally related to anaphylaxis with infusions of Cetuximab are specific for galactose alpha-1,3-galactose. (ii) In the USA, this IgE ab is induced by bites of the tick <i>Amblyomma americanum</i>. (iii) The anaphylactic reactions to food derived from non-primate mammals are delayed in onset by three to five hours. A further important fact is that all humans make a “natural” response to alpha-gal which includes IgM, IgG, and IgA, but not IgE. The clinical features of AGS are recognized in many parts of the world, but different species of ticks are involved. The immune response to tick bites includes T cells specific for tick protein, while IgE producing B cells appear to be derived from B cells specific for IgM or IgG. With repeated tick bites, the T cells develop a strong Th2 signal with IL-4 and IL-13 This obviously relates to IgE production, but may also be relevant to itching after tick bites which can last for weeks. The current hypothesis about the cause of the delayed reactions is based on the time that it takes to digest glycolipids from meat to LDL. The management of AGS symptoms is based on the avoidance of food derived from mammals; however, the only thing that can allow IgE to decrease is avoidance of tick bites.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"332 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281489","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":"Functional Insights From Immunoreceptor Structures","authors":"T. Praveena,&nbsp;Jamie Rossjohn","doi":"10.1111/imr.70043","DOIUrl":"https://doi.org/10.1111/imr.70043","url":null,"abstract":"&lt;p&gt;Generation of immunity is a complex process orchestrated by various immune cells upon recognition of a diverse range of foreign molecules. It has two arms, namely innate and adaptive immunity. The former is the first responder that triggers a non-specific immune response and relies on various cells, including phagocytes, dendritic cells, and Natural Killer cells. The latter is an antigen-specific response and involves T cells and B cells. Innate immunity depends on pattern recognition receptors expressed on the surface of participating cells, including Toll-like receptors, Nod-like receptors, and C-type lectin receptors, whereas adaptive immunity involves specific cell surface receptors like T cell receptors and B antigen cell receptors.&lt;/p&gt;&lt;p&gt;The initial step in the adaptive immune response involves antigen-presenting cell binding, processing, and display of the antigens, which are then recognized by T and B cell antigen receptors, leading to the formation of antigen-receptor complexes on the cell surface. Decades of research have focused on understanding the intricate molecular-level details of this interaction, with the ultimate goal of designing therapeutics that target them. In this regard, structural biology has been an invaluable tool in providing the molecular blueprint of these ligand-receptor interactions.&lt;/p&gt;&lt;p&gt;In this special issue, 14 reviews have been written by leading research groups in the field. These detail the advancements emerging from structural studies, ranging from how T cell receptors (TCRs) become activated, antigen–antibody interactions, to understanding the SARS-CoV-2 receptor binding domain. This review addresses recent structural breakthroughs and concepts in T cell signaling and T cell biology, including unconventional T cells, namely γδ T cells, Mucosal-associated invariant T cells (MAIT cells), integrin receptors, and cytokine binding receptors. Collectively, a broad range of receptor-ligand interactions central to immunity are covered in this issue (Figure 1).&lt;/p&gt;&lt;p&gt;T cells play a crucial role in antigen-specific immune responses through their surface-expressed antigen receptors known as TCRs. They either belong to αβ or γδ T cell lineages, and comprise two chains with variable and constant domains that resemble an immunoglobulin architecture. In recent years, T cell-targeted therapies have shown promise for treating cancer, autoimmunity, and infectious diseases. Success in development of the therapeutics requires in-depth knowledge of receptor structure–function relationships as well as T cell biology. In line with this, Baker and his team [&lt;span&gt;1&lt;/span&gt;] highlight the importance of emerging TCRs that do not abide by the usual established recognition patterns based on structural information. Therefore, as TCR diversity continues to expand, it is paramount to have a thorough understanding of T cell immunity in order to fully harness the immunomodulatory potential of T cells. Davis and colleagues [&lt;span&gt;2&lt;/spa","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"332 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264566","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":"It's Time to Unite: Diversity and Coordination of Thymic Stromal Cells for T Cell Selection and Organ Integrity","authors":"Ryunosuke Muro,&nbsp;Takeshi Nitta","doi":"10.1111/imr.70040","DOIUrl":"https://doi.org/10.1111/imr.70040","url":null,"abstract":"<p>The thymus is a primary lymphoid organ for generating a diverse yet self-tolerant T cell repertoire. Among the thymic stromal cells that create the thymic microenvironment, thymic epithelial cells (TECs) have received the most attention because of their distinctive functions in the repertoire selection of T cells. Other types of thymic stromal cells, such as fibroblasts and endothelial cells, have been less studied, and thus their thymus-specific nature and functions remain unclear. Recent advances in single-cell technologies, multicolor flow cytometry, and sophisticated mouse models have enabled the identification not only of TECs but also of non-TEC stromal cell diversity and the characterization of these cell subpopulations. This review provides a state-of-the-art overview of the thymic microenvironment, focusing on the development and functional diversity of TECs and non-TEC stromal cells. In particular, the recently discovered role of non-TEC stromal cells in thymic organogenesis, T cell selection, and involution and regeneration of the postnatal thymus is highlighted.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"332 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144206398","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":"ILC2 Diversity, Location, and Function in Pulmonary Disease","authors":"Mukesh Verma,&nbsp;Uryan I. Can,&nbsp;R. Lee Reinhardt","doi":"10.1111/imr.70036","DOIUrl":"https://doi.org/10.1111/imr.70036","url":null,"abstract":"<p>Type-2 inflammation is driven by the production of canonical type-2 cytokines IL-4, IL-5, and IL-13. Type-2 cytokines promote mucus production, innate immune cell recruitment, and smooth muscle contractility in mucosal tissues. These hallmarks of type-2 inflammation are important contributors to the weep-and-sweep responses observed in the lung and intestine after epithelial insults. While these type-2 cytokines are generated by a number of innate and adaptive immune cells, group 2 innate lymphoid cells (ILC2) are key early producers of these cytokines and are critical in shaping immune responses in the lung. This review summarizes the role of ILC2 in the lung with specific emphasis on their origins as part of the gut-lung axis, their heterogeneity with respect to unique identities of circulating and tissue resident ILC2 populations, and how these relatively rare immune cells can significantly impact the course of pulmonary disease. We also explore factors that influence ILC2 behavior with respect to activation, migration, and communication with their environment.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"332 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144190771","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":"Thymic Interferons: A Little Goes a Long Way","authors":"Matouš Vobořil,&nbsp;Kristin A. Hogquist","doi":"10.1111/imr.70038","DOIUrl":"https://doi.org/10.1111/imr.70038","url":null,"abstract":"<div>\u0000 \u0000 <p>Central tolerance is an essential process that protects the mammalian immune system from developing autoimmune reactions by forming a self-tolerant repertoire of T cells. The extent of central tolerance depends on the diversity of self-peptide–major histocompatibility complexes that thymocytes encounter on thymic antigen-presenting cells (APCs). Decades of research have demonstrated that medullary thymic epithelial cells (mTECs), a unique type of APC of stromal origin, possess an extraordinary capacity to produce and present thousands of self-peptides to developing thymocytes. This ability is facilitated by various unconventional mechanisms, including AIRE-regulated promiscuous gene expression, mimicry of peripheral cell types, and cooperative antigen transfer between different thymic APCs. Recently, several studies have reported that mTECs and other thymus-resident cells also produce tonic inflammatory signaling, which shapes the thymic microenvironment and expands the repertoire of presented inflammation-associated self-antigens (ISA). In this review, we focus on thymic interferons (IFNs), pro-inflammatory molecules produced as self-antigens by mTECs. Beyond their role as rare self-antigens critical for tolerance induction, IFNs influence the thymic microenvironment by promoting sterile inflammation, regulating the maturation of thymic APCs, and shaping T cell selection. We will discuss the production and regulation of thymic IFNs and their role in APC maturation and T cell selection.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"332 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144171826","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":"Thymflammation: The Role of a Constitutively Active Inflammatory Network and “Ectopic” Cell Types in the Thymus in the Induction of T Cell Tolerance and Beyond","authors":"Taras Kreslavsky","doi":"10.1111/imr.70037","DOIUrl":"https://doi.org/10.1111/imr.70037","url":null,"abstract":"<p>The thymus exhibits constitutive activation of nearly all major inflammatory pathways, including sterile MyD88-dependent signaling and interferon production by mTECs, the presence of cellular and molecular components of type 1, type 2, and type 3 responses, as well as sustained B cell activation. The reasons for the existence of such a complex constitutively active inflammatory network at the site of T cell development—where the initial pathogen encounter is unlikely—have remained enigmatic. We propose that this inflammatory thymic ‘ecosystem’ has evolved to promote immunological tolerance to ‘inflammatory self’—endogenous molecules absent from most peripheral tissues at steady state but upregulated during pathogen invasion. The spatial and temporal overlap with pathogen presence makes the discrimination of the inflammatory self from pathogen-derived molecules a unique challenge for the adaptive immune system. The frequent occurrence of diseases associated with autoantibodies against proinflammatory cytokines underscores the persistent risk of these molecules being misidentified as foreign. Their abundant representation in the thymus, therefore, is likely to be critical for maintaining tolerance. This review explores current insights into the thymic inflammatory network, its cellular and molecular constituents, and their role in the induction of T cell tolerance.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"332 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148641","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":"Intrathymic Regulation of Dendritic Cell Subsets and Their Contributions to Central Tolerance","authors":"Aparna Calindi,&nbsp;Lauren I. R. Ehrlich","doi":"10.1111/imr.70039","DOIUrl":"https://doi.org/10.1111/imr.70039","url":null,"abstract":"<p>Thymic dendritic cells (DCs) are critical mediators of central tolerance, cooperating with medullary thymic epithelial cells (mTECs) and B cells to establish T-cell self-tolerance to the proteome. The DC compartment is highly heterogeneous and is comprised of three major subsets, plasmacytoid dendritic cells (pDCs) and two conventional dendritic cell (cDC) subsets, cDC1 and cDC2. Thymic cDC1 and cDC2 arise from distinct progenitors and access the thymus at different stages of their differentiation, but both become activated by cellular and secreted cues received within the sterile thymus environment. Activated cDC1s and cDC2s have been implicated in presenting distinct types of self-antigens to induce central tolerance. Thus, understanding how the distinct cDC subsets are regulated within the thymus environment will provide important insights into mechanisms governing self-tolerance. Furthermore, the thymic DC compartment undergoes age-associated compositional and transcriptional changes that likely impact the efficiency and quality of central tolerance established over the lifespan. Here, we review recent findings from our lab and others on mechanisms regulating thymic DC activation, the distinct roles of thymic DC subsets in central tolerance, and age-associated changes in thymic DCs that could impact T-cell selection.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"332 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148642","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":"Molecular Insights Into MR1-Mediated T Cell Immunity: Lessons Learned and Unanswered Questions","authors":"Wael Awad,&nbsp;Mohamed R. Abdelaal,&nbsp;Victoria Letoga,&nbsp;James McCluskey,&nbsp;Jamie Rossjohn","doi":"10.1111/imr.70033","DOIUrl":"https://doi.org/10.1111/imr.70033","url":null,"abstract":"<p>The major histocompatibility complex class-I related protein, MR1, is an evolutionarily conserved antigen presenting molecule that binds and displays organic metabolites to T cells, including mucosal associated invariant T (MAIT) cells and diverse MR1-restricted T cells (MR1T). Structural studies have elucidated how MR1 can accommodate a range of chemical scaffolds that arise from foreign, synthetic, and self-metabolites, although the full spectrum of metabolites that MR1 presents remains unclear. Presently, MAIT and MR1T cell recognition of MR1-antigen complexes represents a new immune recognition paradigm and is emerging as a critical player in protective immunity, aberrant immunity, tumor immunity, and tissue repair. Moreover, the limited allelic variation of MR1 makes it an attractive therapeutic target. This review will address the unique features and capability of the MR1 molecule to display several classes of small molecules for T cell surveillance. We will also address the molecular basis underlying MAIT and MR1T TCR recognition of MR1-binding ligands.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"331 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919590","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":"IgE in the Regulation of Adaptive Immune Responses","authors":"Paul Engeroff,&nbsp;Monique Vogel","doi":"10.1111/imr.70030","DOIUrl":"https://doi.org/10.1111/imr.70030","url":null,"abstract":"<div>\u0000 \u0000 <p>Immunoglobulin E (IgE) plays a dual role in the immune system, providing protection against pathogens while also mediating pathological hypersensitivity reactions. Its function is mainly studied in the context of immediate inflammatory responses, where IgE-sensitized effector cells, such as mast cells and basophils, are triggered by a cross-linking antigen. An often-overlooked feature of IgE biology is its strong ability to boost secondary adaptive immune responses, thus acting as a physiological adjuvant. The regulation of these responses is influenced by various factors, including the primary Ig structure, post-translational modifications such as glycosylations, structural properties of the antigens, and the interaction of IgE with immune receptors. Interestingly, IgE not only generates antigen-specific immune responses, but also IgE-specific autoimmune responses. Natural IgG anti-IgE autoantibodies circulate at surprisingly high levels, even in healthy individuals, contributing to the regulation of IgE serum levels and its interaction with receptors. Understanding these emerging concepts, beyond a singular focus on initial IgE production and immediate effector cell activation, could contribute to a better understanding of the immunological functions of IgE. In this review, we aim to provide an overview of current knowledge on IgE immunogenicity. Many open questions remain on the negative and positive feedback mechanisms by which IgE regulates the adaptive immune response, and we hope to inspire future research into the mechanisms underlying IgE-regulated immune responses and their potential implications for therapeutic strategies in hypersensitivity diseases.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"331 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904907","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}