Immunological Reviews最新文献

{"title":"Innate Immune Sensors in Health and Disease","authors":"Prajwal Gurung","doi":"10.1111/imr.70008","DOIUrl":"https://doi.org/10.1111/imr.70008","url":null,"abstract":"<p>The immune system constantly patrols the body, identifying and responding to deviations from homeostasis. These deviations can include pathogens, foreign substances (such as inert particles or allergens), or signs of host tissue damage (e.g., from trauma or radiation). A robust host response is essential to resolve these challenges. Both immune and nonimmune cells work together to initiate these critical responses. All cells express a variety of pattern recognition receptors (PRRs) that detect potential threats. These PRRs recognize molecular patterns associated with pathogens, known as pathogen-associated molecular patterns (PAMPs), or molecular patterns derived from damaged host tissue, known as damage-associated molecular patterns (DAMPs) (Figure 1).</p><p>One of the major classes of pattern recognition receptors (PRRs) includes membrane-bound Toll-like receptors (TLRs). As membrane-bound receptors, TLRs recognize extracellular threats, including PAMPs and DAMPs present in the extracellular milieu or within endosomes. Humans possess 10 functional TLRs, designated TLR1 to TLR10 [<span>1</span>]. In contrast, mice—the most used model system in research—have twelve functional TLRs, including TLR1 to TLR9 and then TLR11 to TLR13 [<span>1</span>]. Similarly, C-type lectin receptors (CLRs) [<span>2</span>] and formyl peptide receptors (FPRs) [<span>3</span>] are membrane-bound PRRs that recognize distinct extracellular PAMPs and DAMPs. Collectively, these membrane-bound PRRs initiate signaling pathways, including nuclear factor kappa B (NFκB), mitogen-activated protein kinases (MAPK) and interferon (IFN) signaling. This activation ultimately leads to the production of pro-inflammatory cytokines and promotes a protective immune response.</p><p>While membrane-bound PRRs effectively detect extracellular PAMPs and DAMPs, they are less suited for sensing intracellular threats. Many pathogens—including viruses, bacteria, and protozoa—have evolved to survive within intracellular niches. Additionally, cellular damage within the intracellular milieu (i.e., damage of organelles) must also be detected, a task that membrane-bound PRRs cannot perform. Fortunately, immune cells are equipped with a diverse array of cytoplasmic PRRs to detect intracellular PAMPs and DAMPs. These cytoplasmic sensors can be broadly classified into three major groups: Nod-like receptors (NLRs), AIM2-like receptors (ALRs) and RIG-I-like receptors (RLRs). Additionally, broad classes of RNA and DNA sensors—including DEAD/H-box helicases and ZBP1—play crucial roles in intracellular immune surveillance. These have been reviewed in this issue and will be discussed in brief below.</p><p>The innate immune response is a double-edged sword. An insufficient immune response can result in uncontrolled infections and impaired tissue repair, whereas an overactive or dysregulated immune response can lead to autoinflammation and immunopathology. Our understanding of the roles of cytoplasmic PRRs in","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431604","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":"Innate Immune Receptors as Dynamic Modulators of Extrafollicular Autoimmune B Cell Response","authors":"Danni Yi-Dan Zhu,&nbsp;Carlos Castrillon,&nbsp;Michael C. Carroll","doi":"10.1111/imr.70005","DOIUrl":"https://doi.org/10.1111/imr.70005","url":null,"abstract":"<div>\u0000 \u0000 <p>The immune system relies on carefully calibrated cellular machineries to enable distinction between endogenous and foreign molecules, with autoimmunity arising when this balance is disrupted. As potent autoantibody factories, B cells are major drivers of many autoimmune diseases. A significant fraction of patients affected by chronic autoimmune diseases such as systemic lupus erythematosus (SLE) exhibit pathogenic accumulation of B-cell subsets that are believed to be derived from the extrafollicular (EF) differentiation pathway. These B-cell subsets, although variously named and exhibiting intrinsic heterogeneity, are all poised producers of autoantibodies that correlate with patient pathophysiology. In addition, they are often characterized by biomarkers known to drive the innate immune response, including toll-like receptors and complement receptors. Although many innate receptors have well-established functions in myeloid cells and other immune cell types, their B cell-specific functions are still under active investigation and are crucial for understanding the molecular pathways that drive B-cell breaks of tolerance. In this review, we summarize studies on innate immune receptors that serve prominent roles in regulating EF B-cell activation in health and autoimmunity. By discussing independent and collaborative functions of these receptors, we hope to provide new perspectives in autoimmune disease signature research.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362576","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":"Signaling Activation and Modulation in Extrafollicular B Cell Responses","authors":"Julian Staniek,&nbsp;Marta Rizzi","doi":"10.1111/imr.70004","DOIUrl":"https://doi.org/10.1111/imr.70004","url":null,"abstract":"<p>The differentiation of naive follicular B cells into either the germinal center (GC) or extrafollicular (EF) pathway plays a critical role in shaping the type, affinity, and longevity of effector B cells. This choice also governs the selection and survival of autoreactive B cells, influencing their potential to enter the memory compartment. During the first 2–3 days following antigen encounter, initially activated B cells integrate activating signals from T cells, Toll-like receptors (TLRs), and cytokines, alongside inhibitory signals mediated by inhibitory receptors. This integration modulates the intensity of signaling, particularly of the PI3K/AKT/mTOR pathway, which plays a central role in guiding developmental decisions. These early signaling events determine whether B cells undergo GC maturation or differentiate rapidly into antibody-secreting cells (ASCs) via the EF pathway. Dysregulation of these signaling pathways—whether through excessive activation or defective regulatory mechanisms—can disrupt the balance between GC and EF fates, predisposing individuals to autoimmunity. Accordingly, aberrant PI3K/AKT/mTOR signaling has been implicated in the defective selection of autoreactive B cells, increasing the risk of autoimmune disease. This review focuses on the signaling events in newly activated B cells, with an emphasis on the induction and regulation of the PI3K/AKT/mTOR pathway. It also highlights gaps in our understanding of how alternative B cell fates are regulated. Both the physiological context and the implications of inborn errors of immunity (IEIs) and complex autoimmune conditions will be discussed in this regard.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362575","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":"A Structural Voyage Toward the Landscape of Humoral and Cellular Immune Escapes of SARS-CoV-2","authors":"Jun Liu,&nbsp;Yan Wu,&nbsp;George F. Gao","doi":"10.1111/imr.70000","DOIUrl":"10.1111/imr.70000","url":null,"abstract":"<div>\u0000 \u0000 <p>The genome-based surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the past nearly 5 years since its emergence has refreshed our understanding of virus evolution, especially on convergent co-evolution with the host. SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations that affect the functional properties of the virus by altering its infectivity, virulence, transmissibility, and interactions with host immunity. This poses a huge challenge to global prevention and control measures based on drug treatment and vaccine application. As one of the key evasion strategies in response to the immune profile of the human population, there are overwhelming amounts of evidence for the reduced antibody neutralization of SARS-CoV-2 variants. Additionally, data also suggest that the levels of CD4⁺ and CD8⁺ T-cell responses against variants or sub-variants decrease in the populations, although non-negligible cross-T-cell responses are maintained. Herein, from the perspectives of structural immunology, we outline the characteristics and mechanisms of the T cell and antibody responses to SARS-CoV and its variants/sub-variants. The molecular bases for the impact of the immune escaping variants on the interaction of the epitopes with the key receptors in adaptive immunity, that is, major histocompatibility complex (MHC), T-cell receptor (TCR), and antibody are summarized and discussed, the knowledge of which will widen our understanding of this pandemic-threatening virus and assist the preparedness for Pathogen X in the future.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187806","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":"Targeting Bottlenecks in Malaria Transmission: Antibody-Epitope Descriptions Guide the Design of Next-Generation Biomedical Interventions","authors":"Randy Yoo,&nbsp;Matthijs M. Jore,&nbsp;Jean-Philippe Julien","doi":"10.1111/imr.70001","DOIUrl":"10.1111/imr.70001","url":null,"abstract":"<p>Malaria continues to pose a significant burden to global health. Thus, a strong need exists for the development of a diverse panel of intervention strategies and modalities to combat malaria and achieve elimination and eradication goals. Deploying interventions that target bottlenecks in the transmission life cycle of the causative agent of malaria, <i>Plasmodium</i> parasites, is an attractive strategy. The development of highly potent antibody-based biologics, including vaccines, can be greatly facilitated by an in-depth molecular understanding of antibody-epitope interactions. Here, we provide an overview of structurally characterized antibodies targeting lead vaccine candidates expressed during the bottlenecks of the <i>Plasmodium</i> life cycle which include the pre-erythrocytic and sexual stages. The repeat region of the circumsporozoite protein (CSP), domain 1 of Pfs230 and domains 1 and 3 of Pfs48/45 are critical <i>Plasmodium</i> regions targeted by the most potent antibodies at the two bottlenecks of transmission, with other promising targets emerging and requiring further characterization.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187807","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":"Inflammasome Activation by RNA Respiratory Viruses: Mechanisms, Viral Manipulation, and Therapeutic Insights","authors":"Tamara S. Rodrigues,&nbsp;Dario S. Zamboni","doi":"10.1111/imr.70003","DOIUrl":"10.1111/imr.70003","url":null,"abstract":"<div>\u0000 \u0000 <p>Respiratory viruses, including SARS-CoV-2, influenza, parainfluenza, rhinovirus, and respiratory syncytial virus (RSV), are pathogens responsible for lower respiratory tract infections, particularly in vulnerable populations such as children and the elderly. Upon infection, these viruses are recognized by pattern recognition receptors, leading to the activation of inflammasomes, which are essential for mediating inflammatory responses. This review discusses the mechanisms by which these RNA respiratory viruses activate inflammasomes, emphasizing the roles of various signaling pathways and components involved in this process. Additionally, we highlight the specific interactions between viral proteins and inflammasome sensors, elucidating how these viruses manipulate the host immune response to facilitate infection. Understanding the dynamics of inflammasome activation in response to respiratory viruses provides critical insights for developing immunomodulatory therapeutic strategies aimed at mitigating inflammation and improving outcomes in respiratory tract infections.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072956","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":"LAG Time in the Era of Immunotherapy—New Molecular Insights Into the Immunosuppression Mechanism of Lymphocyte Activation Gene-3","authors":"Vincent C. Luca","doi":"10.1111/imr.70002","DOIUrl":"10.1111/imr.70002","url":null,"abstract":"<div>\u0000 \u0000 <p>The immune checkpoint receptor lymphocyte activation gene-3 (LAG3) inhibits T-cell activation and was recently validated as a target for cancer immunotherapy. Despite its emergence as a therapeutic target, a lack of molecular-level insight has obscured our understanding of the LAG3 immunosuppression mechanism. This review highlights a series of breakthroughs that have illuminated fundamental aspects of LAG3 molecular biology. Key discoveries include structural insights into LAG3 interactions with ligands and antibodies, mechanistic studies of LAG3 interference with T-cell receptor (TCR) signaling, and the development of novel therapeutics. A particular focus is placed on structure–function relationships for LAG3-targeting drugs, as it has become apparent that several distinct approaches to LAG3 antagonism are viable. In addition to LAG3 antagonists, agonistic LAG3 antibodies and immunostimulatory LAG3 extracellular domains (ECDs) are discussed in the context of current structural and mechanistic data. Collectively, these findings should provide an updated landscape for the design of optimal LAG3-based therapeutics for cancer and autoimmune diseases.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062237","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":"Innate Immunity Never “NODs” Off: NLRs Regulate the Host Anti-Viral Immune Response","authors":"Mackenzie K. Woolls,&nbsp;Madeline D. Mott,&nbsp;Cassandra S. Poole,&nbsp;Julia A. Gregory,&nbsp;Hannah M. Ivester,&nbsp;Irving Coy Allen","doi":"10.1111/imr.13429","DOIUrl":"10.1111/imr.13429","url":null,"abstract":"<p>A robust innate immune response is essential in combating viral pathogens. However, it is equally critical to quell overzealous immune signaling to limit collateral damage and enable inflammation resolution. Pattern recognition receptors are critical regulators of these processes. The cytosolic nucleotide-binding domain leucine-rich repeat (NLR; NOD-like receptor) family of pattern recognition receptors plays essential roles in the sensing of viral pathogen-associated molecular patterns and is best characterized for itsr pro-inflammatory biological functions. Specifically, these include the formation of multi-protein complexes, defined as inflammasomes or NODosomes that regulate the production of IL-1beta, IL-18, and pyroptosis, or the induction of NF-ΚB signaling. While these biological effects are inherently pro-inflammatory, it is also important to recognize that other NLR family members conversely function to negatively regulate inflammation through modulating signaling initiated by other families of pattern recognition receptors. Mechanistically, these unique NLRs also form multiprotein complexes that act to attenuate a variety of biological signaling pathways, such as the inhibition of NF-ΚB. This inhibition facilitates inflammation resolution and functions to restore cellular homeostasis. Despite extensive characterization of individual NLR family members, the mechanisms of immune system regulation are highly nuanced and remain enigmatic. This is especially true for non-inflammasome-forming, regulatory NLRs. Here, we discuss recent findings associated with NLR family members that play essential roles in the host immune response to viruses and mechanisms by which these pattern recognition receptors may function to regulate antiviral immunity.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776368/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057444","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":"Know Your ABCs: Discovery, Differentiation, and Targeting of T-Bet+ B Cells","authors":"Gary M. Winslow,&nbsp;Russell Levack","doi":"10.1111/imr.13440","DOIUrl":"10.1111/imr.13440","url":null,"abstract":"<p>Since their first description in 2008, T-bet+ B cells have emerged as a clinically important B cell subset. Now commonly known as ABCs (Age-associated B Cells), they are uniquely characterized by their expression of the transcription factor T-bet. Indeed, this singular factor defines this B cell subset. This review will describe the discovery of T-bet+ B cells, their role in bacterial infection as T cell-independent (TI) plasmablasts, as well as long-term follicular helper T cell-dependent (TD) IgM+ and switched memory cells (i.e., T-bet+ ABCs), and later discoveries of their role(s) in diverse immunological responses. These studies highlight a critical, although limited, role of T-bet in IgG2a class switching, a function central to the cells' role in immunity and autoimmunity. Given their association with autoimmunity, pharmacological targeting is an attractive strategy for reducing or eliminating the B cells. T-bet+ ABCs express a number of characteristic cell surface markers, including CD11c, CD11b, CD73, and the adenosine 2a receptor (A2aR). Accordingly, A2aR agonist administration effectively targeted T-bet+ ABCs in vivo. Moreover, agonist treatment of lupus-prone mice reduced autoantibodies and disease symptoms. This latter work highlights the potential therapeutic use of adenosine agonists for treating autoimmune diseases involving T-bet+ ABCs.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021366","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 Evolving T Cell Receptor Recognition Code: The Rules Are More Like Guidelines","authors":"George I. Gray,&nbsp;P. Chukwunalu Chukwuma,&nbsp;Bassant Eldaly,&nbsp;W. W. J. Gihan Perera,&nbsp;Chad A. Brambley,&nbsp;Tatiana J. Rosales,&nbsp;Brian M. Baker","doi":"10.1111/imr.13439","DOIUrl":"10.1111/imr.13439","url":null,"abstract":"<div>\u0000 \u0000 <p>αβ T cell receptor (TCR) recognition of peptide–MHC complexes lies at the core of adaptive immunity, balancing specificity and cross-reactivity to facilitate effective antigen discrimination. Early structural studies established basic frameworks helpful for understanding and contextualizing TCR recognition and features such as peptide specificity and MHC restriction. However, the growing TCR structural database and studies launched from structural work continue to reveal exceptions to common assumptions and simplifications derived from earlier work. Here we explore our evolving understanding of TCR recognition, illustrating how structural and biophysical investigations regularly uncover complex phenomena that push against paradigms and expand our understanding of how TCRs bind to and discriminate between peptide/MHC complexes. We discuss the implications of these findings for basic, translational, and predictive immunology, including the challenges in accounting for the inherent adaptability, flexibility, and occasional biophysical sloppiness that characterize TCR recognition.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968962","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}