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  • To TAP or not to TAP: alternative peptides for immunotherapy of cancer
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2020-01-14
    Koen A. Marijt; Thorbald van Hall

    Intracellular processing of antigens is crucial for the generation of T cell immunity towards cancers, since cleaved protein products are the molecular targets of these adaptive lymphocytes. The majority of antigenic peptides requires the TAP transporter to gain access to the peptide loading complex in the ER lumen where they bind MHC class I (MHC-I). This pivotal role of TAP in antigen processing makes the system vulnerable for modifications in cancer cells and indeed human cancers frequently silence this gene epigenetically. Interestingly, TAP-independent processing pathways then become apparent and partly restore MHC class I presentation with alternative peptides. In this review we discuss recent insights on how TAP-independent processing of immunogenic peptides occurs, and how these antigens can be exploited for cancer immunotherapy.

    更新日期:2020-01-15
  • Endogenous TAP-independent MHC-I antigen presentation: not just the ER lumen
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2020-01-11
    Margarita Del Val; Luis C Antón; Manuel Ramos; Víctor Muñoz-Abad; Elena Campos-Sánchez

    Altered and infected cells are eliminated by CD8+ cytotoxic T lymphocytes. This requires production of antigenic peptides mostly in the cytosol, transport to the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP), and cell surface presentation by major histocompatibility complex class I (MHC-I). Strikingly, antigen presentation occurs without TAP, although it is inefficient and associated to human pathology. TAP-independent peptides derive both from membrane and secreted proteins, as well as cytosolic ones. The efficiency of TAP-independent presentation may be impacted by the availability of receptive MHC-I, and in turn by the functional presence in the ER of the peptide-loading complex, itself anchored on TAP. Without TAP, surface expression of human leukocyte antigen (HLA)-B allotypes varies widely, with those presenting a broader peptide repertoire among the most TAP-independent. Much remains to be learned on the alternative cellular pathways for antigen presentation in the absence of TAP.

    更新日期:2020-01-13
  • Cross-presentation of exogenous antigens on MHC I molecules
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2020-01-09
    Jeff D Colbert; Freidrich M Cruz; Kenneth L Rock

    In order to get recognized by CD8 T cells, most cells present peptides from endogenously expressed self or foreign proteins on MHC class I molecules. However, specialized antigen-presenting cells, such as DCs and macrophages, can present exogenous antigen on MHC-I in a process called cross-presentation. This pathway plays key roles in antimicrobial and antitumor immunity, and also immune tolerance. Recent advances have broadened our understanding of the underlying mechanisms of cross-presentation. Here, we review some of these recent advances, including the distinct pathways that result in the cross-priming of CD8 T cells and the source of the class I molecules presenting exogenous peptides.

    更新日期:2020-01-11
  • Selection in the germinal center
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-12-11
    Angelica WY Lau, Robert Brink

    Germinal centers (GCs) are well known for their important role in shaping the secondary B cell repertoire to generate antibodies capable of binding with high-affinity and specificity to foreign antigens. Somatic hypermutation of the Ig variable region genes in GC B cells represents a highly efficient mechanism for generating new antibody variants with increased antigen affinity. To be effective, however, this process needs to be intimately linked with equally efficient processes that positively select high-affinity clones for perpetuation in the GC and, ultimately, for differentiation into plasma cell and memory B cell effector populations. Just as important is the need for mechanisms of negative selection that remove GC B cell clones with unwanted specificities, particularly those that have gained reactivity with self-components. Here, we discuss recent advances in our understanding of the various selective processes that occur within the GC and identify the major questions in this field that remain to be answered.

    更新日期:2019-12-11
  • Metabolic control of B cell immune responses
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-12-01
    Julia Jellusova

    Humoral immunity critically depends on appropriate B cell responses. B cell activation, proliferation, differentiation and antibody secretion are processes carefully orchestrated by a complex network of intracellular signaling pathways and transcription factors. In order to meet the energetic and biosynthetic demands of protein synthesis and cell division, signal transduction pathways reshape the metabolic profile of activated B cells. However, the relationship between signaling and metabolism is by no means unidirectional. Emerging evidence suggests that shifts in available fuel sources and intracellular metabolite concentrations profoundly impact cell fate decisions. The reciprocal regulation of cell signaling and metabolism could potentially be exploited to curb immune dysfunction in metabolic disorders or to antagonize autoimmunity and B cell malignancies.

    更新日期:2019-12-02
  • New insights on T-cell self-tolerance
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-11-28
    Jaeu Yi, Takeshi Kawabe, Jonathan Sprent

    Self-tolerance of T cells is maintained by a combination of thymic negative selection and suppression by T regulatory cells (Tregs); both processes are driven by recognition of self MHC ligands. Treg function ensures that most T cells remain quiescent as naïve cells, but enables some T cells to proliferate and differentiate into cells with a memory phenotype (MP). In this review, we discuss how Tregs shape this compartmentalization of T cells into subsets of naïve and MP T cells.

    更新日期:2019-11-29
  • New function of zebrafish regulatory T cells in organ regeneration
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-11-22
    Kazu Kikuchi

    Zebrafish can efficiently regenerate complex tissue structures with a highly developed innate and adaptive immune system, which provides a model to investigate the roles of immune cells in tissue repair and regeneration. Two groups recently reported zebrafish mutants deficient in a forkhead box P3 (FOXP3) ortholog, which helped reveal the conserved immunosuppressive function of zebrafish FOXP3 in vivo. Zebrafish FOXP3 defines the development of a subset of T cell lineage with the conserved gene expression profile of mammalian regulatory T cells (Tregs). In damaged organs, zebrafish Tregs rapidly migrate to the injury site, where they promote the proliferation of regeneration precursor cells by producing tissue-specific regenerative factors through a distinct mechanism from the canonical anti-inflammatory pathway. These findings illuminate the potential for using zebrafish as an effective model in Treg research and demonstrate organ-specific roles for Tregs in maintaining proregenerative capacity that could potentially be harnessed for use in diverse regeneration therapies.

    更新日期:2019-11-26
  • Editorial overview: Autoimmunity: A new frontier awaits.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2018-12-14
    Daniel B Stetson

    更新日期:2019-11-01
  • The long and the short of it: insights into the cellular source of autoantibodies as revealed by B cell depletion therapy.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2018-11-06
    Malika Hale,David J Rawlings,Shaun W Jackson

    High titers of pathogenic autoantibodies are a hallmark of many autoimmune diseases. However, much remains unknown about the self-reactive plasma cells that are key mediators of disease. We propose a model in which the varying efficacy of precursor B cell depletion for the treatment of humoral autoimmunity can be explained by differences in the relative contributions of pathogenic antibodies by short-lived versus long-lived plasma cells. Beyond therapeutic considerations, this model suggests that we can infer the cellular source of disease-associated autoantibodies by the durability of serum titers following B cell depletion. Data from clinical trials and animal models across different autoimmune diseases may provide useful insights into the lifespan, lifestyle and fate of autoreactive plasma cells.

    更新日期:2019-11-01
  • B cell targeted therapies in autoimmune disease.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-11-17
    Jennifer L Barnas,Richard John Looney,Jennifer H Anolik

    PURPOSE OF REVIEW FDA-approved B cell-targeted therapy has expanded to a multitude of autoimmune diseases ranging from organ specific diseases, like pemphigus and multiple sclerosis, to systemic diseases such as ANCA-associated vasculitis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In this review, we discuss the variability in response to B cell-targeted therapies with a focus on the diversity of human B cells and plasma cells, and will discuss several of the promising new B cell-targeted therapies. RECENT FINDING The pathogenic roles for B cells include autoantibody-dependent and autoantibody-independent functions whose importance may vary across diseases or even in subsets of patients with the same disease. Recent data have further demonstrated the diversity of human B cell subsets that contribute to disease as well as novel pathways of B cell activation in autoimmune disease. The importance of eliminating autoreactive B cells and plasma cells will be discussed, as well as new approaches to do so. SUMMARY The past several years has witnessed significant advances in our knowledge of human B cell subsets and function. This has created a nuanced picture of the diverse ways B cells contribute to autoimmunity and an ever-expanding armamentarium of B cell-targeted therapies.

    更新日期:2019-11-01
  • Pathogenic memory plasma cells in autoimmunity.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-11-02
    Hyun-Dong Chang,Koji Tokoyoda,Bimba Hoyer,Tobias Alexander,Laleh Khodadadi,Henrik Mei,Thomas Dörner,Falk Hiepe,Gerd-Rüdiger Burmester,Andreas Radbruch

    更新日期:2019-11-01
  • Macrophage ontogeny in the control of adipose tissue biology.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : null
    Nehemiah Cox,Frederic Geissmann

    Macrophages are found in large numbers in the adipose tissue where they closely associate with the adipocytes and the vasculature. Adipose tissue macrophages are a heterogenous population of cells with 'hard wired' diversity brought upon by distinct developmental lineages. The purpose of this review is to provide a brief history of macrophages in control of adipose tissue metabolism with the emphasis on the importance of macrophage ontogeny.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Mina: a Th2 response regulator meets TGFβ.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2014-10-06
    Meenu R Pillai,Shangli Lian,Mark Bix

    The JmjC protein Mina is an important immune response regulator. Classical forward genetics first discovered its immune role in 2009 in connection with the development of T helper 2 (Th2) cells. This prompted investigation into Mina's role in the two best-studied contexts where Th2 responses are essential: atopic asthma and helminth expulsion. In work focused on a mouse model of atopic asthma, Mina deficiency was found to ameliorate airway hyper-resistance and pulmonary inflammation. And, in a case-control study genetic variation at the human MINA locus was found to be associated with the development of childhood atopic asthma. Although the underlying cellular and molecular mechanism of Mina's involvement in pulmonary inflammation remains unknown, our recent work on parasitic helminth expulsion suggests the possibility that, rather than T cells, epithelial cells responding to TGFβ may play the dominant role. Here we review the growing body of literature on the emerging Mina pathway in T cells and epithelial cells and attempt to set these into a broader context.

    更新日期:2019-11-01
  • E3 ubiquitin ligases for MHC molecules.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2009-02-11
    Satoshi Ishido,Eiji Goto,Yohei Matsuki,Mari Ohmura-Hoshino

    Recently, novel E3 ubiquitin ligases that target MHC molecules for lysosomal degradation have been discovered by several groups. All these E3s are membrane-bound and possess a variant type RING domain, termed the RING-CH or RING variant (RINGv) domain. They belong to a new E3 family designated Modulator of Immune Recognition (MIR), based on the name of the first identified family members. The discovery of the MIR family has provided fresh insight into viral pathogenesis and immune regulation.

    更新日期:2019-11-01
  • Interactions between environmental pollutants and genetic susceptibility in asthma risk.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-08-31
    Hanna Johansson,Tesfaye B Mersha,Eric B Brandt,Gurjit K Khurana Hershey

    Exposure to air pollution is associated with enhanced risk of developing asthma, notably in the presence of genetic risk factors. Interaction analyses have shown that both outdoor and indoor air pollution interact with genetic variability to increase the incidence of asthma. In this review, we summarize recent progress in candidate gene-based studies, as well as genome-wide gene-air pollution interaction studies. Advances in epigenetics have provided evidence for DNA methylation as a mediator in gene-air pollution interactions. Emerging strategies for study design and statistical analyses may improve power in future studies. Improved air pollution exposure assessment methods and asthma endo-typing can also be expected to increase the ability to detect biologically driven gene-air pollution interaction effects.

    更新日期:2019-11-01
  • Roles for the adaptive immune system in Parkinson's and Alzheimer's diseases.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-08-21
    Cecilia S Lindestam Arlehamn,Francesca Garretti,David Sulzer,Alessandro Sette

    Neurodegenerative diseases, such as Parkinson's and Alzheimer's, affect millions of people and pose major personal and socioeconomic burdens. The causes of neurodegeneration are mostly unknown, although current efforts have described an autoimmune aspect to these diseases. Here we discuss recent findings that shed light on the involvement of the adaptive immune system in Parkinson's and Alzheimer's diseases, and provide a model and outlook for further investigation of T cell responses in neurodegenerative disease. We focus on the identification of T cell epitopes from proteins involved in disease pathogenesis and describe the identification of α-synuclein-specific epitopes in Parkinson's disease which provided a crucial link between disease susceptibility and T cell recognition.

    更新日期:2019-11-01
  • Human lung tissue resident memory T cells in health and disease.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-07-03
    Mark E Snyder,Donna L Farber

    The human lung contains a heterogeneous population of immune cells which mediate protective responses, maintain tissue homeostasis, but can also promote immunopathology in disease. The majority of T cells in the human lung are tissue resident memory T cells (TRM) which have been shown in mouse models to provide vital roles in the protection against multiple respiratory pathogens, and contribute to heterosubtypic protection in the context of vaccination. In this review, we will discuss recent studies in humans identifying lung TRM, their role in maintaining tissue homeostasis, and emerging evidence implicating TRM in anti-tumor immunity and immune surveillance as well as their potential for immunopathology in chronic airway inflammation.

    更新日期:2019-11-01
  • Human inborn errors of immunity to infection affecting cells other than leukocytes: from the immune system to the whole organism.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-05-24
    Shen-Ying Zhang,Emmanuelle Jouanguy,Qian Zhang,Laurent Abel,Anne Puel,Jean-Laurent Casanova

    Studies of vertebrate immunity have traditionally focused on professional cells, including circulating and tissue-resident leukocytes. Evidence that non-professional cells are also intrinsically essential (i.e. not via their effect on leukocytes) for protective immunity in natural conditions of infection has emerged from three lines of research in human genetics. First, studies of Mendelian resistance to infection have revealed an essential role of DARC-expressing erythrocytes in protection against Plasmodium vivax infection, and an essential role of FUT2-expressing intestinal epithelial cells for protection against norovirus and rotavirus infections. Second, studies of inborn errors of non-hematopoietic cell-extrinsic immunity have shown that APOL1 and complement cascade components secreted by hepatocytes are essential for protective immunity to trypanosome and pyogenic bacteria, respectively. Third, studies of inborn errors of non-hematopoietic cell-intrinsic immunity have suggested that keratinocytes, pulmonary epithelial cells, and cortical neurons are essential for tissue-specific protective immunity to human papillomaviruses, influenza virus, and herpes simplex virus, respectively. Various other types of genetic resistance or predisposition to infection in human populations are not readily explained by inborn variants of genes operating in leukocytes and may, therefore, involve defects in other cells. The probing of this unchartered territory by human genetics is reshaping immunology, by scaling immunity to infection up from the immune system to the whole organism.

    更新日期:2019-11-01
  • Pertussis vaccines and protective immunity.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-05-12
    Parul Kapil,Tod J Merkel

    Despite high vaccine coverage, reported cases of pertussis have increased steadily over the last twenty years. This resurgence has stimulated interest in host responses to pertussis infection and vaccination with the goal of developing more effective next-generation vaccines and vaccination strategies. Optimal protection against Bordetella pertussis appears to be multifactorial requiring both humoral and cellular responses. Natural infection and whole-cell pertussis vaccination induce Th1 and Th17-dominated responses. In contrast, acellular vaccines induce Th2-dominated responses. Available immunological data indicate that while antibodies provide protection against disease, Th1 and Th17-mediated immune responses are required for bacterial clearance and long-lasting protection. The nature of the priming in children appears to be important in modulating bias and durability of immune responses required to provide protection against B. pertussis. This review summarizes the current understanding of differences in immune responses and their role in protection against B. pertussis following infection or vaccination.

    更新日期:2019-11-01
  • Early innate immune responses to bacterial LPS.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2016-11-15
    Charles V Rosadini,Jonathan C Kagan

    A mammalian receptor for bacterial lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4), plays a beneficial role in controlling bacterial infections, but is also a main driver of aberrant inflammation in lethal sepsis. As a result, investigation of TLR4 signaling has been a major area of research. Despite this focus, our understanding of the mechanisms that regulate TLR4 activities remains primitive. Nowhere is our knowledge of TLR4 biology more lacking than at the receptor-proximal level, where many factors act in concert to regulate LPS signaling. Several recent studies have begun filling these gaps in our knowledge. In this review, we discuss the importance of these receptor proximal activities in the spatiotemporal regulation of TLR4 signaling, and suggest interesting areas for future research.

    更新日期:2019-11-01
  • The new vaccines: building viruses that elicit antitumor immunity.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 1996-10-01
    N P Restifo

    Whereas cancer cells are poor immunogens, some viruses are capable of eliciting powerful and lifelong immunity. Recombinant viruses and plasmid DNA encoding tumor-associated antigens can elicit powerful and specific immune responses that can be enhanced by the use of cytokines and costimulatory molecules. These immune responses have destroyed growing tumor cells in experimental animal models. For the first time, immunotherapeutic strategies that employ recombinant viruses are being tested in clinical trials with cancer patients.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • How a farming environment protects from atopy.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-09-10
    Julie Deckers,Bart N Lambrecht,Hamida Hammad

    It is now well established that the exposure to certain environments such as farms has the potential to protect from the development of allergies later in life. This protection is achieved when repeated exposure to the farming environment occurs early in life, but persists when children spend sufficient amount of time in contact with livestock and hay, and drink unpasteurized milk. The capacity of farm dust to protect from allergy development lies, amongst others, in the microbe composition in the farm. These protective microbes release various metabolites and cell wall components that change farmers' home dust composition, when compared to urbanized home dust. Additionally, they can colonize various barrier sites (skin, lung, intestine) in farmers' children, leading to persistent changes in the way their immune system and their barrier cells respond to environmental allergens.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • NextGen cell-based immunotherapies in cancer and other immune disorders.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-05-10
    Camillia S Azimi,Qizhi Tang,Kole T Roybal,Jeffrey A Bluestone

    T lymphocyte and other cell therapies have the potential to transform how we treat cancers and other diseases that have few therapeutic options. Here, we review the current progress in engineered T cell therapies and look to the future of what will establish cell therapy as the next pillar of medicine. The tools of synthetic biology along with fundamental knowledge in cell biology and immunology have enabled the development of approaches to engineer cells with enhanced capacity to recognize and treat disease safely and effectively. This along with new modes of engineering cells with CRISPR and strategies to make universal 'off-the-shelf' cell therapies will provide more rapid, flexible, and cheaper translation to the clinic.

    更新日期:2019-11-01
  • Studying interactions between dendritic cells and T cells in vivo.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2019-03-19
    Aleksey Chudnovskiy,Giulia Pasqual,Gabriel D Victora

    Antigen presentation is the key first step in the establishment of an antigen-specific T cell response. Among professional antigen presenting cells (APCs), dendritic cells (DCs) are the major population responsible for the priming of both CD4+ and CD8+ naïve T cells. This priming requires physical interaction between the DC and the T cell; during which signals are exchanged that determine both the magnitude and the quality of the ensuing response. The nature of these signals varies widely depending on the nature of the antigen, the anatomical site in which they take place, and the phenotype of the antigen-presenting DC, making the study of the dynamics, microanatomical distribution and phenotypic variation of DCs a key part of our understanding of adaptive immunity. Here, we provide a brief survey of how our view of T cell activation by DCs has evolved over recent years as intravital multiphoton microscopy and other emerging technologies have expanded our ability to study these events in vivo.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Metabolic reprograming of anti-tumor immunity.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2017-04-17
    Madhusudhanan Sukumar,Rigel J Kishton,Nicholas P Restifo

    Immunotherapies designed to trigger T cell destruction of tumor cells can result in sustained and complete responses in patients whose cancers were resistant to available treatment options. Evidence suggests that powering the T cell response - how T cells generate energy - plays an important role in their effectiveness. Furthermore the metabolism of T cells can be modulated to improve their anti-cancer activities. In this review, we will discuss the key metabolic properties of anti-cancer T cells, along with potential strategies to enhance immunotherapy through the modulation of T cell metabolism.

    更新日期:2019-11-01
  • Endoplasmic reticulum stress in beta cells and autoimmune diabetes.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2016-10-09
    Amy L Clark,Fumihiko Urano

    Type 1 diabetes results from the autoimmune destruction of pancreatic β cells, leading to insulin deficiency and hyperglycemia. Although multiple attempts have been made to slow the autoimmune process using immunosuppressive or immunomodulatory agents, there are still no effective treatments that can delay or reverse the progression of type 1 diabetes in humans. Recent studies support endoplasmic reticulum (ER) as a novel target for preventing the initiation of the autoimmune reaction, propagation of inflammation, and β cell death in type 1 diabetes. This review highlights recent findings on ER stress in β cells and development of type 1 diabetes and introduces potential new treatments targeting the ER to combat this disorder.

    更新日期:2019-11-01
  • The development of adult innate lymphoid cells.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2016-02-13
    Qi Yang,Avinash Bhandoola

    Innate lymphoid cells (ILC) are a specialized family of effector lymphocytes that transcriptionally and functionally mirror effector subsets of T cells, but differ from T cells in that they lack clonally distributed adaptive antigen receptors. Our understanding of this family of lymphocytes is still in its infancy. In this review, we summarize current understanding and discuss recent insights into the cellular and molecular events that occur during early ILC development in adult mice. We discuss how these events overlap and diverge with the early development of adaptive T cells, and how they may influence the molecular and functional properties of mature ILC.

    更新日期:2019-11-01
  • The role of microbiota in cancer therapy.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2016-01-29
    Ernesto Perez-Chanona,Giorgio Trinchieri

    The relationship between the host and the commensal microbiota regulates physiological functions including inflammation and immunity and it has been scrutinized in the context of cancer. While viruses and bacterial species have been implicated in oncogenesis, commensal microbes also have a beneficial role in the fight against cancer. Therapy efficacy, including adoptive T cell transfer, alkylating agents and immune checkpoint blockers, relies on immunity that receives its education from the gut microbiota. In cancer therapy with immunostimulating oligonucleotides and platinum salts, the microbiota also modulates the response by priming for the release of pro-inflammatory factors and reactive oxygen species, respectively. This new information offers promising clinical possibilities of modulating cancer therapy and its toxic side effects by targeting the microbiota.

    更新日期:2019-11-01
  • Localized signals that regulate transendothelial migration.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2015-11-20
    William A Muller

    Transendothelial migration (TEM) of leukocytes is the step in leukocyte emigration in which the leukocyte actually leaves the blood vessel to carry out its role in the inflammatory response. It is therefore, arguably the most critical step in emigration. This review focuses on two of the many aspects of this process that have seen important recent developments. The adhesion molecules, PECAM (CD31) and CD99 that regulate two major steps in TEM, do so by regulating specific signals. PECAM initiates the signaling pathway responsible for the calcium flux that is required for TEM. Calcium enters through the cation channel TRPC6 and recruits the first wave of trafficking of membrane from the lateral border recycling compartment (LBRC). CD99 signals through soluble adenylate cyclase to activate protein kinase A to recruit a second wave of LBRC trafficking. Another process that is critical for TEM is transient removal of VE-cadherin from the site of TEM. However, the local signaling pathways that are responsible for this appear to be different from those that open the junctions to increase vascular permeability.

    更新日期:2019-11-01
  • Identifying genetic determinants of autoimmunity and immune dysregulation.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2015-10-05
    Carrie L Lucas,Michael J Lenardo

    Common autoimmune diseases are relatively heterogeneous with both genetic and environmental factors influencing disease susceptibility and progression. As the populations in developed countries age, these chronic diseases will become an increasing burden in human suffering and health care costs. By contrast, rare immune diseases that are severe and develop early in childhood are frequently monogenic and fully penetrant, often with a Mendelian inheritance pattern. Although these may be incompatible with survival or cured by hematopoietic stem cell transplantation, we will argue that they constitute a rich source of genetic insights into immunological diseases. Here, we discuss five examples of well-studied Mendelian disease-causing genes and their known or predicted roles in conferring susceptibility to common, polygenic diseases of autoimmunity. Mendelian disease mutations, as experiments of nature, reveal human loci that are indispensable for immune regulation and, therefore, most promising as therapeutic targets.

    更新日期:2019-11-01
  • Genetics of allergy and allergic sensitization: common variants, rare mutations.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2015-09-20
    Klaus Bønnelykke,Rachel Sparks,Johannes Waage,Joshua D Milner

    Our understanding of the specific genetic lesions in allergy has improved in recent years due to identification of common risk variants from genome-wide association studies (GWAS) and studies of rare, monogenic diseases. Large-scale GWAS have identified novel susceptibility loci and provided information about shared genetics between allergy, related phenotypes and autoimmunity. Studies of monogenic diseases have elucidated critical cellular pathways and protein functions responsible for allergy. These complementary approaches imply genetic mechanisms involved in Th2 immunity, T-cell differentiation, TGFβ signaling, regulatory T-cell function and skin/mucosal function as well as yet unknown mechanisms associated with newly identified genes. Future studies, in combination with data on gene expression and epigenetics, are expected to increase our understanding of the pathogenesis of allergy.

    更新日期:2019-11-01
  • Novel antigens for RSV vaccines.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2015-06-13
    Barney S Graham,Kayvon Modjarrad,Jason S McLellan

    Respiratory syncytial virus (RSV) remains a leading global cause of infant mortality and adult morbidity. Infection, which recurs throughout life, elicits only short-lived immunity. The development of a safe and efficacious vaccine has, thus far, been elusive. Recent technological advances, however, have yielded promising RSV vaccine candidates that are based on solving atomic-level structures of surface glycoproteins interacting with neutralizing antibodies. The class I fusion glycoprotein, F, serves as the primary antigenic component of most vaccines, and is the target of the only licensed monoclonal antibody product used to reduce the frequency of severe disease in high-risk neonates. However, success of prior F-based vaccines has been limited by the lack of understanding how the conformational rearrangement between a metastable prefusion F (pre-F) and a stable postfusion F (post-F) affected the epitope content. Neutralizing epitopes reside on both conformations, but those specific to pre-F are far more potent than those previously identified and present on post-F. The solution of the pre-F structure and its subsequent characterization and stabilization illustrates the value of a structure-based approach to vaccine development, and provides hope that a safe and effective RSV vaccine is possible.

    更新日期:2019-11-01
  • CD1d-dependent endogenous and exogenous lipid antigen presentation.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2015-03-26
    Rosanna M McEwen-Smith,Mariolina Salio,Vincenzo Cerundolo

    Invariant natural killer T (iNKT) cells recognize endogenous and exogenous lipids in the context of CD1d molecules, and through the activation and maturation of dendritic cells and B cells, can significantly enhance priming of antigen-specific T and B cell responses. Recent findings have provided important insights into the recognition of several novel endogenous lipids by iNKT cells, and into the mechanisms controlling their generation and loading onto CD1d molecules. In this review we discuss these latest findings and describe the role of autophagy in iNKT cell development and activation.

    更新日期:2019-11-01
  • Suppression of antigen presentation by IL-10.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2015-01-20
    Sharad K Mittal,Paul A Roche

    Regulated antigen presentation to immune cells determines the effectiveness of an immune response. IL-10 is an immunosuppressive cytokine that regulates immune responses by inhibiting the ability of APCs to present antigens to T cells in a variety of ways. The mechanisms of IL-10-mediated immunosuppression include interference in TLR-mediated or IFNγ-mediated dendritic cell (DC) and macrophage activation as well as direct induction of genes that suppress APC function. In this review we will discuss current studies exploring the molecular mechanisms by which IL-10 suppresses APC function.

    更新日期:2019-11-01
  • Defining features of protective CD4 T cell responses to Mycobacterium tuberculosis.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2014-07-08
    Shunsuke Sakai,Katrin D Mayer-Barber,Daniel L Barber

    CD4 T cells are critical for control of Mycobacterium tuberculosis (Mtb) infection and represent the best hope for vaccine-elicited protection. However, little is understood about the properties of Mtb-specific CD4 T cells that mediate control, and the lack of correlates of protection present a significant barrier to the rational development of new vaccination and therapeutic strategies which are sorely needed. Here we discuss the features of protective CD4 T cells including recent evidence for IFN-γ dependent and independent mechanisms of protection, poor protection by terminally differentiated cells and the importance of T cell migratory capacity for the control of Mtb infection.

    更新日期:2019-11-01
  • Spontaneous activation of RNA-sensing pathways in autoimmune disease.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2014-01-24
    Steve P Crampton,Silvia Bolland

    Multiple intracellular RNA sensing innate immune pathways have been linked to autoimmune disease. RNA-related ligands taken up by the endocytic pathway activate TLRs, and affect primarily immune cells. This type of activation is enhanced by nucleic acid-specific antibodies and induces an inflammatory program. In contrast, spontaneous activation of cytoplasmic RNA sensing pathways targets mostly non-hematopoietic tissues and their effect on autoimmune disease is secondary to the release of interferon in the circulation. The fact that pathologies result from spontaneous activation of innate pathways implies that endogenous RNA ligands that might be sensed as pathogenic are commonly found in both immune and non-immune cells.

    更新日期:2019-11-01
  • Structures of pattern recognition receptors reveal molecular mechanisms of autoinhibition, ligand recognition and oligomerization.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2014-01-15
    Watchalee Chuenchor,Tengchuan Jin,Geoffrey Ravilious,T Sam Xiao

    Pattern recognition receptors (PRRs) are essential sentinels for pathogens or tissue damage and integral components of the innate immune system. Recent structural studies have provided unprecedented insights into the molecular mechanisms of ligand recognition and signal transduction by several PRR families at distinct subcellular compartments. Here we highlight some of the recent discoveries and summarize the common themes that are emerging from these exciting studies. Better mechanistic understanding of the structure and function of the PRRs will improve future prospects of therapeutic targeting of these important innate immune receptors.

    更新日期:2019-11-01
  • The deleterious role of basophils in systemic lupus erythematosus.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2013-11-12
    Christophe Pellefigues,Nicolas Charles

    Systemic lupus erythematosus is a complex autoimmune disease of multifactorial origins. All compartments of the immune system appear to be affected, at least in some way, and to contribute to disease pathogenesis. Because of an escape from negative selection autoreactive T and B cells accumulate in SLE patients leading to the production of autoantibodies mainly raised against nuclear components and their subsequent deposition into target organs. We recently showed that basophils, in an IgE and IL-4 dependent manner, contribute to SLE pathogenesis by amplifying autoantibody production. Here, we summarize what we have learned about the deleterious role of basophils in lupus both in a mouse model and in SLE patients. We discuss which possible pathways could be involved in basophil activation and recruitment to secondary lymphoid organs during SLE, and how basophils may amplify autoantibody production.

    更新日期:2019-11-01
  • Mechanisms regulating the targeting and activity of activation induced cytidine deaminase.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2013-11-12
    David J Fear

    Activation induced cytidine deaminase (AID) plays a central role in the vertebrate adaptive immune response, initiating immunoglobulin (Ig) somatic hypermutation (SHM) and class-switch recombination (CSR). AID converts deoxycytosine (dC) in the DNA to deoxyuridine (dU), causing a DNA base-pairing mismatch. How this mismatch is recognised and resolved determines whether the site will undergo mutation, recombination or high-fidelity repair. Although AID action is essential for antibody diversification it is also known to act upon many non-Ig genes where it can cause tumourigenic mutations and translocations. Although much is known about the pathways of Ig diversification, there is still very little known about the mechanisms that target AID to its sites of action and regulate the different repair processes that can participate at these sites.

    更新日期:2019-11-01
  • Lineage relationship of effector and memory T cells.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2013-10-24
    Nicholas P Restifo,Luca Gattinoni

    Adaptive immunity is characterized by the ability to form long-lived immunological memory. Upon re-exposure to antigen, memory T cells respond more rapidly and robustly than naïve T cells, providing better clearance of pathogens. Recent reviews have reinforced the text-book view that memory T cells arise from effector cells. Although this notion is teleologically appealing, emerging data are more consistent with a model where naïve cells directly develop into memory cells without transitioning through an effector stage. A clear understanding of the lineage relationships between memory and effector cells has profound implications for the design of vaccines and for the development of effective T cell-based therapies.

    更新日期:2019-11-01
  • Comparative immunology: allorecognition and variable surface receptors outside the jawed vertebrates.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2013-07-31
    Marc S Dionne

    Allograft rejection is one of several undesirable consequences of the adaptive nature of the mammalian immune response. This review examines adaptive immune responses and allorecognition in animals with very different immune responses - jawless vertebrates, arthropods, and two distinct colonial marine invertebrates - with the goal of understanding how immune adaptation and allograft rejection are linked, and conversely how a system works where allograft rejection is a desired outcome rather than an unforeseen consequence.

    更新日期:2019-11-01
  • Transcriptional regulation of effector and memory CD8+ T cell fates.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2013-06-12
    James E D Thaventhiran,Douglas T Fearon,Luca Gattinoni

    Immunity to intracellular pathogens and cancer relies on the generation of robust CD8(+) T cell effector responses as well as the establishment of immunological memory. During a primary immune response CD8(+) T cells experience diverse extracellular environmental cues and cell-cell interactions that trigger downstream transcriptional programs ultimately guiding a CD8(+) T cell to undertake either an effector or a memory cell fate. Here, we discuss our current understanding of the signaling pathways and transcriptional networks that regulate effector and memory commitment in CD8(+) T lymphocytes.

    更新日期:2019-11-01
  • Development and function of group 2 innate lymphoid cells.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2013-04-09
    Jennifer A Walker,Andrew N J McKenzie

    The innate lymphoid cell (ILC) family has recently expanded with the discovery of type-2 innate lymphoid cells (ILC2). These cells arise from lymphoid progenitors in the bone marrow and, under the control of the transcriptional regulators RORα and Gata3, they mature to give rise to IL-5, IL-9 and IL-13 producing ILC2. These cells are critical components of the innate immune response to parasitic worm infections and have also been implicated in the pathogenesis of asthma and allergy. Recent advances in our understanding of the molecular regulation of ILC2 development and function now present the opportunity to develop new genetic models to assess ILC2 immune function and to investigate possible therapeutic interventions.

    更新日期:2019-11-01
  • Vaccine against autoimmune disease: can helminths or their products provide a therapy?
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2013-03-08
    Paola Zaccone,Anne Cooke

    There is an increasing interest in exploiting the immunomodulatory effects of helminths and their products in treatment of diseases such as allergy, autoimmunity and inflammatory bowel disease. Detailed examination of the ways in which helminth derived products interact with the host immune system and with host physiology has revealed that these may be multifaceted and have almost certainly arisen following co-evolution of helminths and their hosts. Clinical trials have been initiated with encouraging results in the treatment of inflammatory bowel disease and also Multiple Sclerosis. Identification of key pathways that are manipulated by helminths to ameliorate ongoing inflammatory conditions increases the prospect of developing novel therapies for the treatment and possible prevention of a range of debilitating and life threatening conditions.

    更新日期:2019-11-01
  • Dietary and commensal derived nutrients: shaping mucosal and systemic immunity.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2012-08-04
    Sean P Spencer,Yasmine Belkaid

    The intestine serves as the primary site of nutrient absorption in the body while also harboring the highest burden of commensal microflora and representing a major portal of pathogen exposure. As such, the immune network of the intestine relies on both dietary and commensal derived signals to guide appropriate function. Recent advances highlight the role of dietary derived nutrients and commensal derived metabolites in shaping gastrointestinal immunity. In particular, vitamin A has been shown to have dominant and pleiotropic effects in the intestine. In addition, dietary derived AHR ligands and commensal derived metabolites are now emerging as important players in mucosal immunity. Thus nutrition, commensal microflora and the mucosal immune system are all intimately connected.

    更新日期:2019-11-01
  • Susceptibility and immunity to helminth parasites.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2012-07-17
    Rick M Maizels,James P Hewitson,Katherine A Smith

    Parasitic helminth infection remains a global health problem, whilst the ability of worms to manipulate and dampen the host immune system is attracting interest in the fields of allergy and autoimmunity. Much progress has been made in the last two years in determining the cells and cytokines involved in induction of Type 2 immunity, which is generally protective against helminth infection. Innate cells respond to 'alarmin' cytokines (IL-25, IL-33, TSLP) by producing IL-4, IL-5 and IL-13, and this sets the stage for a more potent subsequent adaptive Th2 response. CD4+ Th2 cells then drive a suite of type 2 anti-parasite mechanisms, including class-switched antibodies, activated leukocytes and innate defence molecules; the concerted effects of these multiple pathways disable, degrade and dislodge parasites, leading to their destruction or expulsion.

    更新日期:2019-11-01
  • T cell control of malaria pathogenesis.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2012-06-05
    Philip J Spence,Jean Langhorne

    Transmission of Plasmodium from mosquito to the mammalian host leads to a clinically silent pre-erythrocytic stage of malaria infection, and subsequent cyclical erythrocytic invasion associated with disease. Recent evidence demonstrates that it is the interplay between CD4+ and CD8+ T cells, and the regulation of their response, throughout infection that dictates immunity and the pathogenesis of malaria. The elicited T cell response is context dependent, influenced by diverse host and parasite factors, necessitating the development of a unifying model of T cell potential during Plasmodium infection. Only then can we predict their capacity to dictate the outcome of human disease.

    更新日期:2019-11-01
  • Telomeres and immune competency.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2012-05-26
    Nan-ping Weng

    Telomeres are essential for the integrity of chromosomes and for cellular replication. Attrition of telomeres occurs during DNA replication owing to the inability of conventional DNA polymerase to replicate chromosomal termini and the insufficient compensation for telomere loss by telomerase, an enzyme that synthesizes telomeric DNA. A number of genetic defects have been described in humans and in animal models that cause accelerated telomere attrition, in turn leading to severe phenotypes of hematopoietic and other proliferating cells. Telomere length, most frequently measured as an average value in heterogeneous peripheral blood leukocyte populations in humans, has been associated with a wide range of health conditions and diseases of immune and non-immune cells. Here, I review recent studies of telomere length dynamics with particular relevance to immune function.

    更新日期:2019-11-01
  • Properties of end-stage human T cells defined by CD45RA re-expression.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2012-05-05
    Sian M Henson,Natalie E Riddell,Arne N Akbar

    Persistent viral infections, inflammatory syndromes and ageing all induce the accumulation of highly differentiated CD45RA re-expressing memory T cells. These cells increase during ageing, especially in individuals who are infected with cytomegalovirus (CMV). These cells have decreased proliferative capacity, increased activation of senescence signalling pathways and greater susceptibility to apoptosis in vitro. However these cells are capable of multiple effector functions and thus bear all the hallmarks of short-lived effector T cells. This indicates that senescence signalling may govern the unique characteristics of effector T cells. In this article, we address the functional and migratory properties of these T cells and mechanisms that are involved in their generation. Finally we assess the potential for manipulation of their activity and whether this may improve immune function during ageing.

    更新日期:2019-11-01
  • CD4-CD8 differentiation in the thymus: connecting circuits and building memories.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2012-03-06
    Yumei Xiong,Rémy Bosselut

    The proper choice of the CD4-helper or CD8-cytotoxic lineages by developing T cells is crucial for the generation of an antigen-responsive and functionally fit T cell repertoire. Here we present a brief overview of the transcriptional control of this process, with emphasis on two issues. The study of Cd4 expression, that had previously generated important paradigms for transcriptional regulation in eukaryotic cells, now brings new twists to the concept of 'epigenetic memory'. And connections are emerging between transcriptional regulators critical for commitment to either lineage. The present review attempts to integrate these findings and discusses the still elusive mechanisms that match CD4-CD8 lineage differentiation to MHC specificity.

    更新日期:2019-11-01
  • Helper T cell diversity and plasticity.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2012-02-22
    Shingo Nakayamada,Hayato Takahashi,Yuka Kanno,John J O'Shea

    CD4(+) helper T cells play crucial roles for host defense and immune-mediated disease by their ability to differentiate into specialized subsets. These subsets attain restricted patterns of cytokine secretion and specific expression of master transcription factors in response to microbial pathogens. Classically, the various helper CD4(+) T cell subsets have been viewed as terminally differentiated lineages with limited flexibility. However, following the recognition of new subsets, there is increased recognition of plasticity. In this review, we highlight recent advances that pertain to this topic and the mechanisms that contribute to helper CD4(+) T cell differentiation and plasticity.

    更新日期:2019-11-01
  • Regulation of lymphocyte development and function by RNA-binding proteins.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2012-02-14
    Martin Turner,Daniel Hodson

    Lymphocyte development requires cells to progress through a series of stages, each associated with changes in gene expression. Intense effort has been invested into characterising the dynamic networks of transcription factors underlying these regulated changes. Whilst transcription factors determine the tempo at which mRNA is produced, recent results highlight the importance of the selective regulation of mRNA decay and translation in regulating gene expression. These processes are regulated by sequence-specific RNA-binding proteins (RBP) as well as noncoding RNA such as microRNAs. RNA-binding proteins are emerging as important regulators of cell fate and function in both developing and mature lymphocytes. At the molecular level the function of RNA-binding proteins is integrated with signal transduction pathways that also govern gene transcription.

    更新日期:2019-11-01
  • IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2011-09-06
    Wei Liao,Jian-Xin Lin,Warren J Leonard

    Interleukin-2 (IL-2) is a pleiotropic cytokine that drives T-cell growth, augments NK cytolytic activity, induces the differentiation of regulatory T cells, and mediates activation-induced cell death. Along with IL-4, IL-7, IL-9, IL-15, and IL-21, IL-2 shares the common cytokine receptor γ chain, γ(c), which is mutated in humans with X-linked severe combined immunodeficiency. Herein, we primarily focus on the recently discovered complex roles of IL-2 in broadly modulating T cells for T helper cell differentiation. IL-2 does not specify the type of Th differentiation that occurs; instead, IL-2 modulates expression of receptors for other cytokines and transcription factors, thereby either promoting or inhibiting cytokine cascades that correlate with each Th differentiation state. In this fashion, IL-2 can prime and potentially maintain Th1 and Th2 differentiation as well as expand such populations of cells, whereas it inhibits Th17 differentiation but also can expand Th17 cells.

    更新日期:2019-11-01
  • Regulatory T cells as modulators of chronic allograft dysfunction.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2011-07-15
    Fadi Issa,Deepak Chandrasekharan,Kathryn J Wood

    Chronic allograft dysfunction (CAD) in solid organ transplantation is a principal cause of patient morbidity and late allograft loss. The pathogenesis of CAD is largely secondary to chronic damage by the adaptive immune system and long-term immunosuppression. Manipulating these factors may be possible with the use of regulatory T cells (Treg), which have the ability to suppress specific immune responses and therefore potentially remove the need for immunosuppressive drugs. Studies of CAD in experimental models have demonstrated the capacity for both mouse and human Treg cellular therapy to prevent the development of some manifestations of CAD. Furthermore, a role for Treg has been demonstrated in clinically tolerant transplant patients. Certain immunosuppressive therapies are also proving to be 'Treg friendly' and may be helpful in promoting Treg while maintaining other immunosuppressive activity. With this in mind, monitoring for biomarkers of operational tolerance with tailored immunosuppressive therapy or controlled weaning in conjunction with Treg cellular therapy may be a useful strategy to pursue.

    更新日期:2019-11-01
  • Immune responses in the skin in old age.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2011-06-28
    Milica Vukmanovic-Stejic,Malcolm H A Rustin,Janko Nikolich-Zugich,Arne N Akbar

    A marked increase in the susceptibility to cutaneous infections and malignancies has been observed in older humans indicating that cutaneous immunity becomes defective with age. In this review we will focus on recent developments in the understanding of age-related changes in immune function of the skin with a particular emphasis on how alterations in the interaction between cells involved in innate and adaptive immunity leads to decreased cutaneous antigen-specific T cell immunosurveillance.

    更新日期:2019-11-01
  • Targeting of AID-mediated sequence diversification to immunoglobulin genes.
    Curr. Opin. Immunol. (IF 7.667) Pub Date : 2011-02-08
    Naga Rama Kothapalli,Sebastian D Fugmann

    Activation-induced cytidine deaminase (AID) is a key enzyme for antibody-mediated immune responses. Antibodies are encoded by the immunoglobulin genes and AID acts as a transcription-dependent DNA mutator on these genes to improve antibody affinity and effector functions. An emerging theme in field is that many transcribed genes are potential targets of AID, presenting an obvious danger to genomic integrity. Thus there are mechanisms in place to ensure that mutagenic outcomes of AID activity are specifically restricted to the immunoglobulin loci. Cis-regulatory targeting elements mediate this effect and their mode of action is probably a combination of immunoglobulin gene specific activation of AID and a perversion of faithful DNA repair towards error-prone outcomes.

    更新日期:2019-11-01
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