Immunological Reviews最新文献

{"title":"Recognition of Self and Viral Ligands by NK Cell Receptors","authors":"Roy A. Mariuzza,&nbsp;Pragya Singh,&nbsp;Sharanbasappa S. Karade,&nbsp;Salman Shahid,&nbsp;Vijay Kumar Sharma","doi":"10.1111/imr.13435","DOIUrl":"10.1111/imr.13435","url":null,"abstract":"<p>Natural killer (NK) cells are essential elements of the innate immune response against tumors and viral infections. NK cell activation is governed by NK cell receptors that recognize both cellular (self) and viral (non-self) ligands, including MHC, MHC-related, and non-MHC molecules. These diverse receptors belong to two distinct structural families, the C-type lectin superfamily and the immunoglobulin superfamily. NK receptors include Ly49s, KIRs, LILRs, and NKG2A/CD94, which bind MHC class I (MHC-I) molecules, and NKG2D, which binds MHC-I paralogs such MICA and ULBP. Other NK receptors recognize tumor-associated antigens (NKp30, NKp44, NKp46), cell–cell adhesion proteins (KLRG1, CD96), or genetically coupled C-type lectin-like ligands (NKp65, NKR-P1). Additionally, cytomegaloviruses have evolved various immunoevasins, such as m157, m12, and UL18, which bind NK receptors and act as decoys to enable virus-infected cells to escape NK cell-mediated lysis. We review the remarkable progress made in the past 25 years in determining structures of representatives of most known NK receptors bound to MHC, MHC-like, and non-MHC ligands. Together, these structures reveal the multiplicity of solutions NK receptors have developed to recognize these molecules, and thereby mediate crucial interactions for regulating NK cytolytic activity by self and viral ligands.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918829","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":"Z-Nucleic Acid Sensing and Activation of ZBP1 in Cellular Physiology and Disease Pathogenesis","authors":"Sanchita Mishra,&nbsp;Ayushi Amin Dey,&nbsp;Sannula Kesavardhana","doi":"10.1111/imr.13437","DOIUrl":"10.1111/imr.13437","url":null,"abstract":"<div>\u0000 \u0000 <p>Z-nucleic acid binding protein 1 (ZBP1) is an innate immune sensor recognizing nucleic acids in Z-conformation. Upon Z-nucleic acid sensing, ZBP1 triggers innate immune activation, inflammation, and programmed cell death during viral infections, mice development, and inflammation-associated diseases. The Zα domains of ZBP1 sense Z-nucleic acids and promote RIP-homotypic interaction motif (RHIM)-dependent signaling complex assembly to mount cell death and inflammation. The studies on ZBP1 spurred an understanding of the role of Z-form RNA and DNA in cellular and physiological functions. In particular, short viral genomic segments, endogenous retroviral elements, and 3′UTR regions are likely sources of Z-RNAs that orchestrate ZBP1 functions. Recent seminal studies identify an intriguing association of ZBP1 with adenosine deaminase acting on RNA-1 (ADAR1), and cyclic GMP-AMP synthase (cGAS) in regulating aberrant nucleic acid sensing, chronic inflammation, and cancer. Thus, ZBP1 is an attractive target to aid the development of specific therapeutic regimes for disease biology. Here, we discuss the role of ZBP1 in Z-RNA sensing, activation of programmed cell death, and inflammation. Also, we discuss how ZBP1 coordinates intracellular perturbations in homeostasis, and Z-nucleic acid formation to regulate chronic diseases and cancer.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918831","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":"Biophysical and Structural Features of αβT-Cell Receptor Mechanosensing: A Paradigmatic Shift in Understanding T-Cell Activation","authors":"Robert J. Mallis,&nbsp;Kristine N. Brazin,&nbsp;Jonathan S. Duke-Cohan,&nbsp;Aoi Akitsu,&nbsp;Hanna M. Stephens,&nbsp;Ana C. Chang-Gonzalez,&nbsp;Daniel J. Masi,&nbsp;Evan H. Kirkpatrick,&nbsp;Elizabeth L. Holliday,&nbsp;Yinnian Feng,&nbsp;Katarzyna J. Zienkiewicz,&nbsp;Jonathan J. Lee,&nbsp;Vincenzo Cinella,&nbsp;Kaveri I. Uberoy,&nbsp;Kemin Tan,&nbsp;Gerhard Wagner,&nbsp;Haribabu Arthanari,&nbsp;Wonmuk Hwang,&nbsp;Matthew J. Lang,&nbsp;Ellis L. Reinherz","doi":"10.1111/imr.13432","DOIUrl":"10.1111/imr.13432","url":null,"abstract":"<p>αβT cells protect vertebrates against many diseases, optimizing surveillance using mechanical force to distinguish between pathophysiologic cellular alterations and normal self-constituents. The multi-subunit αβT-cell receptor (TCR) operates outside of thermal equilibrium, harvesting energy via physical forces generated by T-cell motility and actin-myosin machinery. When a peptide-bound major histocompatibility complex molecule (pMHC) on an antigen presenting cell is ligated, the αβTCR on the T cell leverages force to form a catch bond, prolonging bond lifetime, and enhancing antigen discrimination. Under load, the αβTCR undergoes reversible structural transitions involving partial unfolding of its clonotypic immunoglobulin-like (Ig) domains and coupled rearrangements of associated CD3 subunits and structural elements. We postulate that transitions provide critical energy to initiate the signaling cascade via induction of αβTCR quaternary structural rearrangements, associated membrane perturbations, exposure of CD3 ITAMs to phosphorylation by non-receptor tyrosine kinases, and phase separation of signaling molecules. Understanding force-mediated signaling by the αβTCR clarifies long-standing questions regarding αβTCR antigen recognition, specificity and affinity, providing a basis for continued investigation. Future directions include examining atomistic mechanisms of αβTCR signal initiation, performance quality, tissue compliance adaptability, and T-cell memory fate. The mechanotransduction paradigm will foster improved rational design of T-cell based vaccines, CAR-Ts, and adoptive therapies.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744257/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913395","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":"Structural Immunology of SARS-CoV-2","authors":"Meng Yuan,&nbsp;Ian A. Wilson","doi":"10.1111/imr.13431","DOIUrl":"10.1111/imr.13431","url":null,"abstract":"<p>The SARS-CoV-2 spike (S) protein has undergone significant evolution, enhancing both receptor binding and immune evasion. In this review, we summarize ongoing efforts to develop antibodies targeting various epitopes of the S protein, focusing on their neutralization potency, breadth, and escape mechanisms. Antibodies targeting the receptor-binding site (RBS) typically exhibit high neutralizing potency but are frequently evaded by mutations in SARS-CoV-2 variants. In contrast, antibodies targeting conserved regions, such as the S2 stem helix and fusion peptide, exhibit broader reactivity but generally lower neutralization potency. However, several broadly neutralizing antibodies have demonstrated exceptional efficacy against emerging variants, including the latest omicron subvariants, underscoring the potential of targeting vulnerable sites such as RBS-A and RBS-D/CR3022. We also highlight public classes of antibodies targeting different sites on the S protein. The vulnerable sites targeted by public antibodies present opportunities for germline-targeting vaccine strategies. Overall, developing escape-resistant, potent antibodies and broadly effective vaccines remains crucial for combating future variants. This review emphasizes the importance of identifying key epitopes and utilizing antibody affinity maturation to inform future therapeutic and vaccine design.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890721","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 Integrin Receptors: From Discovery to Structure to Medicines","authors":"M. Amin Arnaout","doi":"10.1111/imr.13433","DOIUrl":"10.1111/imr.13433","url":null,"abstract":"<div>\u0000 \u0000 <p>Innate immune cells perform vital tasks in detecting, seeking, and eliminating invading pathogens, thus ensuring host survival. However, loss of function of these cells or their overactive response to tissue injury often causes serious ailments. It is, therefore, crucial to understand at a basic level how these cells function in health and disease. A major step toward this goal came from studies I conducted in the late 1970s investigating the cause of life-threatening bacterial infections in a pediatric patient. This work led us to trace this disease to the inability of the patient's neutrophils to seek and clear infections due to an inherited deficiency in leukocyte adhesion caused by the loss of a plasma membrane glycoprotein complex now known as CD11/CD18 or β2 integrins. I followed this work by determining the 3-dimensional structures of integrins. These studies provided the foundation for understanding the unique properties of integrins in mediating bidirectional cell adhesion signaling and enabled a structure-guided design of compounds to dial down overactive integrins in common disorders, including thromboinflammatory and autoimmune diseases.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142890724","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":"The Effector Functions of Antibodies","authors":"Marc Daëron","doi":"10.1111/imr.13428","DOIUrl":"10.1111/imr.13428","url":null,"abstract":"&lt;p&gt;“Antibody” is one of those specialists' words that became common language. Everyone knows that antibodies protect against infectious diseases, especially since the COVID-19 pandemic swept across the world. Everyone, or almost, even knows what antibodies look like. Their anthropomorphic Y shape has become an iconic symbol that most societies of immunology have included in their logo. What antibodies actually are, however, is not so clear in everyone's mind, as judged by media which often confuse serum with vaccine. What antibodies do and how they work is another question. Their well-known ability to recognize specific antigens with each of their two “arms” is often thought to be enough to protect; even by scientists, sometimes by immunologists. Whatever how, antibodies protect, and when they have pathogenic effects, these are viewed as the unfortunate consequences of targeting errors such as in allergic and autoimmune diseases, or collateral damages such as in inflammatory diseases.&lt;/p&gt;&lt;p&gt;Antibodies are also well known as tools. Due to their exquisite specificity, antibodies have proven unrivaled diagnostic tools and they are used in a variety of techniques adopted by all medical disciplines and beyond. Due to their powerful biological properties, antibodies have been increasingly used as therapeutic tools with amazing efficiencies. This is not new: antibodies saved thousands of children from diphtheria and many more wounded soldiers from tetanus at the beginning of the 20th century, when they were nothing but elusive substances in immune serum. They are well-known molecules now and, as serum therapy for deadly infectious diseases yesterday, humanized monoclonal antibodies have provided long-sought cures for cancers with a poor prognosis today. Not without side effects, though. But antibodies can be engineered genetically to enhance their expected effects and to decrease their unwanted effects.&lt;/p&gt;&lt;p&gt;Why, therefore, put together another series of review articles on such well-known molecules? As stated in its title, this volume of &lt;i&gt;Immunological Reviews&lt;/i&gt; is focused on the &lt;i&gt;effector functions&lt;/i&gt; of antibodies. Antibodies are bi-functional molecules: They can not only recognize antigens; they can also act on them. How they do so is poorly known by immunologists, except those who work specifically on the subject. Yet, antibodies are the main effectors of adaptive immunity, at least quantitatively: 10 mg/mL IgG and 2–3 mg/mL IgA circulate in the blood stream—and much more are present in tissues since 80% immunoglobulin-secreting plasma cells of the whole body produce mucosal IgA. How do these antibodies deal with pathogens and commensals? How can they both prevent infections and tolerate microbiotas without inducing devastating inflammatory reactions? How antibodies induced by vaccines exert their protective effects?&lt;/p&gt;&lt;p&gt;This volume deals with the effector functions of antibodies not only in health, but also in disease. If they protect aga","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"328 1","pages":"6-12"},"PeriodicalIF":7.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13428","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805741","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":"Fc Effector Function of Immune Checkpoint Blocking Antibodies in Oncology","authors":"Romane Martineau,&nbsp;Sandrine Susini,&nbsp;Aurelien Marabelle","doi":"10.1111/imr.13427","DOIUrl":"10.1111/imr.13427","url":null,"abstract":"<p>Antagonistic monoclonal antibodies (mAbs) targeting inhibitory immune checkpoints have revolutionized the field of oncology. CTLA-4, PD-1, and LAG3 are three co-inhibitory receptors, which can be expressed by subsets of T cells and which play a role in the regulation of adaptive immune responses. Blocking these immune checkpoints receptors (or their ligands) with antagonistic antibodies can lead to tumor regressions and lasting remissions in some patients with cancer. Two anti-CTLA4, six anti-PD1, three anti-PD-L1, and one anti-LAG3 antibodies are currently approved by the FDA and EMA. Their mechanism of action, safety, and efficacy are linked to their affinity with Fc gamma receptors (FcγR) (so called “effector functions”). The anti-CTLA-4 antibodies ipilimumab (IgG1) and tremilimumab (IgG2a), and the anti-PD-L1 avelumab (IgG1) have isotypes with high affinity for activating FcγR and thereby can induce ADCC/ADCP. The effector function is required for the in vivo efficacy of anti-CTLA4 antibodies. For anti-PD(L)1 antibodies, where a pure antagonistic function (“checkpoint blockade”) is sufficient, some mAbs are IgG1 but have been mutated in their Fc sequence (e.g., durvalumab and atezolizumab) or are IgG4 (e.g., nivolumab and pembrolizumab) to have low affinity for FcγR. Here, we review the impact of FcγR effector function on immune checkpoint blockers safety and efficacy in oncology.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"328 1","pages":"334-349"},"PeriodicalIF":7.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13427","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811691","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":"Established and Emerging Roles of DEAD/H-Box Helicases in Regulating Infection and Immunity","authors":"Michael Parthun,&nbsp;Matthew E. Long,&nbsp;Emily A. Hemann","doi":"10.1111/imr.13426","DOIUrl":"10.1111/imr.13426","url":null,"abstract":"<p>The sensing of nucleic acids by DEAD/H-box helicases, specifically retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), plays a critical role in inducing antiviral immunity following infection. However, this DEAD/H-box helicase family includes many additional proteins whose immune functions have not been investigated. While numerous DEAD/H-box helicases contribute to antiviral immunity, they employ diverse mechanisms beyond the direct sensing of nucleic acids. Some members have also been identified to play proviral (promoting virus replication/propagation) roles during infections, regulate other non-viral infections, and contribute to the regulation of autoimmunity and cancer. This review synthesizes the known and emerging functions of the broader DEAD/H-box helicase family in immune regulation and highlights ongoing efforts to target these proteins therapeutically.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"329 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764932","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":"Immunoglobulin A Antibodies: From Protection to Harmful Roles","authors":"Patrick J. Gleeson,&nbsp;Niels O. S. Camara,&nbsp;Pierre Launay,&nbsp;Agnès Lehuen,&nbsp;Renato C. Monteiro","doi":"10.1111/imr.13424","DOIUrl":"10.1111/imr.13424","url":null,"abstract":"<p>Immunoglobulin A (IgA) is the most abundantly produced antibody in humans. IgA is a unique class of immunoglobulin due to its multiple molecular forms, and a defining difference between the two subclasses: IgA1 has a long hinge-region that is heavily O-glycosylated, whereas the IgA2 hinge-region is shorter but resistant to bacterial proteases prevalent at mucosal sites. IgA is essential for immune homeostasis and education. Mucosal IgA plays a crucial role in maintaining the integrity of the mucosal barrier by immune exclusion of pathobionts while facilitating colonization with certain commensals; a large part of the gut microbiota is coated with IgA. In the circulation, monomeric IgA that has not been engaged by antigen plays a discrete role in dampening inflammatory responses. Protective and harmful roles of IgA have been studied over several decades, but a new understanding of the complex role of this immunoglobulin in health and disease has been provided by recent studies. Here, we discuss the physiological and pathological roles of IgA with a special focus on the gut, kidneys, and autoimmunity. We also discuss new IgA-based therapeutic approaches.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"328 1","pages":"171-191"},"PeriodicalIF":7.5,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.13424","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692267","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 Technical Advances Changed the Concept of Antibodies","authors":"Bartlomiej Swiatczak,&nbsp;Gregor P. Greslehner,&nbsp;Martin Zach","doi":"10.1111/imr.13425","DOIUrl":"10.1111/imr.13425","url":null,"abstract":"<div>\u0000 \u0000 <p>Shaped by advances in scientific instrumentation and experimental techniques, the concept of antibody has undergone profound transformations throughout the history of immunology. Serological assays, separation techniques, protein fragmentation techniques, molecular biology techniques, and other methodological innovations did not only serve to produce data on the structure and function of these molecules but, by framing antibodies into a unique facet of experimental investigation, were effectively redefining and reconceptualizing these molecules for the scientific community. The characteristics and properties of antibodies observed in experimental settings were often directly extrapolated to their presumed nature in living organisms, as exemplified by the literal identification of antibodies with a gamma electrophoretic fraction in the 1930s. Stemming from parallel advances in related fields such as molecular biology and biochemistry, the introduction of novel techniques was driving shifts in the field of immunology, establishing novel frameworks of theoretical conceptualization and understanding. Technological innovation in experimental techniques continues to shape our view of these molecules, driving progress in both basic immunology and therapeutic applications.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"328 1","pages":"39-48"},"PeriodicalIF":7.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680034","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}