Advances in Immunology最新文献

Gasdermins are effectors of pyroptosis downstream of diverse signaling pathways. Emerging evidence suggests that a number of post-translational modifications regulate the function of gasdermins in pyroptosis, a highly inflammatory form of cell death, and lytic or non-lytic secretion of intracellular contents. These include processing by different caspases and other proteases that may activate or suppress pyroptosis, ubiquitination by a bacterial E3 ligase that suppresses pyroptosis as an immune evasion mechanism, modifications at Cys residues in mammalian or microbial gasdermins that promote or inhibit pyroptosis, and potential phosphorylation that represses pyroptosis. Such diverse regulatory mechanisms by host and microbial proteases, ubiquitin ligases, acyltransferases, kinases and phosphatases may underlie the divergent physiological and pathological functions of gasdermins, and furnish opportunities for therapeutic targeting of gasdermins in infectious diseases and inflammatory disorders.

Dendritic cells (DCs) are crucial mediators that bridge the innate and adaptive immune responses. Cellular rewiring of metabolism is an emerging regulator of the activation, migration, and functional specialization of DC subsets in specific microenvironments and immunological conditions. DCs undergo metabolic adaptation to exert immunogenic or tolerogenic effects in different contexts. Also, beyond their intracellular metabolic and signaling roles, metabolites and nutrients mediate the intercellular crosstalk between DCs and other cell types, and such crosstalk orchestrates DC function and immune responses. Here, we provide a comprehensive review of the metabolic regulation of DC biology in various contexts and summarize the current understanding of such regulation in directing immune homeostasis and inflammation, specifically with respect to infections, autoimmunity, tolerance, cancer, metabolic diseases, and crosstalk with gut microbes. Understanding context-specific metabolic alterations in DCs may identify mechanisms for physiological and pathological functions of DCs and yield potential opportunities for therapeutic targeting of DC metabolism in many diseases.

Myeloid cells, particularly macrophages, act as the frontline responders to infectious agents and initiate inflammation. While the molecular mechanisms driving inflammatory responses have primarily focused on pattern recognition by myeloid cells and subsequent transcriptional events, it is crucial to note that post-transcriptional regulation plays a pivotal role in this process. In addition to the transcriptional regulation of innate immune responses, additional layers of intricate network of post-transcriptional mechanisms critically determine the quantity and duration of key inflammatory products and thus the outcome of immune responses. A multitude of mechanisms governing post-transcriptional regulation in innate immunity have been uncovered, encompassing RNA alternative splicing, mRNA stability, and translational regulation. This review encapsulates the current insights into the post-transcriptional regulation of inflammatory genes within myeloid cells, with particular emphasis on translational regulation during inflammation. While acknowledging the advancements, we also shed light on the existing gaps in immunological research pertaining to post-transcriptional levels and propose perspectives that controlling post-transcriptional process may serve as potential targets for therapeutic interventions in inflammatory diseases.

Dendritic cells (DCs) orchestrate T cell responses by presenting antigenic peptides on major histocompatibility complex (MHC) and providing costimulation and other instructive signals. Professional antigen presenting cells (APCs), including DCs, are uniquely capable of generating and presenting peptide antigens derived from exogenous proteins. In addition to these canonical cross-presentation and MHC-II presentation pathways, APCs can also display exogenous peptide/MHC (p/MHC) acquired from neighboring cells and extracellular vesicles (EVs). This process, known as MHC cross-dressing, has been implicated in the regulation of T cell responses in a variety of in vivo contexts, including allogeneic solid organ transplantation, tumors, and viral infection. Although the occurrence of MHC cross-dressing has been clearly demonstrated, the importance of this antigen presentation mechanism continues to be elucidated. The contribution of MHC cross-dressing to overall antigen presentation has been obfuscated by the fact that DCs express the same MHC alleles as all other cells in the host, making it difficult to distinguish p/MHC generated within the DC from p/MHC acquired from another cell. As a result, much of what is known about MHC cross-dressing comes from studies using allogeneic organ transplantation and bone marrow chimeric mice, though recent development of mice bearing conditional knockout MHC and β2-microglobulin alleles should facilitate substantial progress in the coming years. In this review, we highlight recent advances in our understanding of MHC cross-dressing and its role in activating T cell responses in various contexts, as well as the experimental insights into the mechanism by which it occurs.

Cross-presentation is the culmination of complex subcellular processes that allow the processing of exogenous proteins and the presentation of resultant peptides on major histocompatibility class I (MHC-I) molecules to CD8 T cells. Dendritic cells (DCs) are a cell type that uniquely specializes in cross-presentation, mainly in the context of viral or non-viral infection and cancer. DCs have an extensive network of endovesicular pathways that orchestrate the biogenesis of an ideal cross-presentation compartment where processed antigen, MHC-I molecules, and the MHC-I peptide loading machinery all meet. As a central conveyor of information to CD8 T cells, cross-presentation allows cross-priming of T cells which carry out robust adaptive immune responses for tumor and viral clearance. Cross-presentation can be canonical or noncanonical depending on the functional status of the transporter associated with antigen processing (TAP), which in turn influences the vesicular route of MHC-I delivery to internalized antigen and the cross-presented repertoire of peptides. Because TAP is a central node in MHC-I presentation, it is targeted by immune evasive viruses and cancers. Thus, understanding the differences between canonical and noncanonical cross-presentation may inform new therapeutic avenues against cancer and infectious disease. Defects in cross-presentation on a cellular and genetic level lead to immune-related disease progression, recurrent infection, and cancer progression. In this chapter, we review the process of cross-presentation beginning with the DC subsets that conduct cross-presentation, the signals that regulate cross-presentation, the vesicular trafficking pathways that orchestrate cross-presentation, the modes of cross-presentation, and ending with disease contexts where cross-presentation plays a role.

Interleukin-15 is a pleiotropic cytokine type I four alpha-helical bundle cytokine that along with IL-2, IL-4, IL-7, IL-9, and IL-21 shares the common cytokine receptor γ chain, γ_c. IL-15 is vital for the development, survival, and expansion of natural killer cells and for the development of CD8⁺ memory T cells. Whereas other family γ_c cytokines signal by directly binding to their target cells, IL-15 is distinctive in that it binds to IL-15Rα, a sushi domain containing binding protein that is expressed on a number of cell types, including monocytes and dendritic cells as well as T cells, and then is trans-presented to responding cells that express IL-2Rβ and γ_c. This distinctive mechanism for IL-15 relates to its role in signaling in the context of cell-cell interactions and signaling synapses. The actions of IL-15 and ways of manipulating its actions to potential therapeutic benefit are discussed.

Most antibody produced by humans originates from mucosal B cell responses. The rules, mechanisms, and outcomes of this process are distinct from B cell responses to infection. Within the context of the intestine, we discuss the induction of follicular B cell responses by microbiota, the development and maintenance of mucosal antibody-secreting cells, and the unusual impacts of mucosal antibody on commensal bacteria. Much remains to be learned about the interplay between B cells and the microbiota, but past and present work hints at a complex, nuanced relationship that may be critical to the way the mammalian gut fosters a beneficial microbial ecosystem.

Despite effective spike-based vaccines and monoclonal antibodies, the SARS-CoV-2 pandemic continues more than two and a half years post-onset. Relentless investigation has outlined a causative dynamic between host-derived antibodies and reciprocal viral subversion. Integration of this paradigm into the architecture of next generation antiviral strategies, predicated on a foundational understanding of the virology and immunology of SARS-CoV-2, will be critical for success. This review aims to serve as a primer on the immunity endowed by antibodies targeting SARS-CoV-2 spike protein through a structural perspective. We begin by introducing the structure and function of spike, polyclonal immunity to SARS-CoV-2 spike, and the emergence of major SARS-CoV-2 variants that evade immunity. The remainder of the article comprises an in-depth dissection of all major epitopes on SARS-CoV-2 spike in molecular detail, with emphasis on the origins, neutralizing potency, mechanisms of action, cross-reactivity, and variant resistance of representative monoclonal antibodies to each epitope.

Barrier tissues are the primary site of infection for pathogens likely to cause future pandemics. Tissue-resident lymphocytes can rapidly detect pathogens upon infection of barrier tissues and are critical in preventing viral spread. However, most vaccines fail to induce tissue-resident lymphocytes and are instead reliant on circulating antibodies to mediate protective immunity. Circulating antibody titers wane over time following vaccination leaving individuals susceptible to breakthrough infections by variant viral strains that evade antibody neutralization. Memory B cells were recently found to establish tissue residence following infection of barrier tissues. Here, we summarize emerging evidence for the importance of tissue-resident memory B cells in the establishment of protective immunity against viral and bacterial challenge. We also discuss the role of tissue-resident memory B cells in regulating the progression of non-infectious diseases. Finally, we examine new approaches to develop vaccines capable of eliciting barrier immunity.

Autoimmune diseases (ADs) often arise from a combination of genetic and environmental triggers that disrupt the immune system's capability to properly tolerate body self-antigens. Familial studies provided the earliest insights into the risk loci of such diseases, while genome-wide association studies (GWAS) significantly broadened the horizons. A drug targeting a prominent pathological pathway can be applied to multiple indications sharing overlapping mechanisms. Advances in genomic technologies used in genetic studies provide critical insights into future research on gene-environment interactions in autoimmunity. This Review summarizes the history and recent advances in the understanding of genetic susceptibility to ADs and related immune disorders, including coronavirus disease 2019 (COVID-19), and their indications for the development of diagnostic or prognostic markers for translational applications.