Advances in Immunology最新文献

The complement system consists of three pathways (alternative, classical, and lectin) that play a fundamental role in immunity and homeostasis. The multifunctional role of the complement system includes direct lysis of pathogens, tagging pathogens for phagocytosis, promotion of inflammatory responses to control infection, regulation of adaptive cellular immune responses, and removal of apoptotic/dead cells and immune complexes from circulation. A tight regulation of the complement system is essential to avoid unwanted complement-mediated damage to the host. This regulation is ensured by a set of proteins called complement regulatory proteins. Deficiencies or malfunction of these regulatory proteins may lead to pro-thrombotic hematological diseases, renal and ocular diseases, and autoimmune diseases, among others. This review focuses on the importance of two complement regulatory proteins of the alternative pathway, Factor H and properdin, and their role in human diseases with an emphasis on: (a) characterizing the main mechanism of action of Factor H and properdin in regulating the complement system and protecting the host from complement-mediated attack, (b) describing the dysregulation of the alternative pathway as a result of deficiencies, or mutations, in Factor H and properdin, (c) outlining the clinical findings, management and treatment of diseases associated with mutations and deficiencies in Factor H, and (d) defining the unwanted and inadequate functioning of properdin in disease, through a discussion of various experimental research findings utilizing in vitro, mouse and human models.

B cells are integral components of the mammalian immune response as they have the ability to generate antibodies against an almost infinite array of antigens. Over the past several decades, significant scientific progress has been made in understanding that this enormous B cell diversity contributes to pathogen clearance. However, our understanding of the humoral response to solid tumors and to tumor-specific antigens is unclear. In this review, we first discuss how B cells interact with other cells in the tumor microenvironment and influence the development and progression of various solid tumors. The ability of B lymphocytes to generate antibodies against a diverse repertoire of antigens and subsequently tailor the humoral immune response to specific pathogens relies on their ability to undergo genomic alterations during their development and differentiation. We will discuss key transforming events that lead to the development of B cell lymphomas. Overall, this review provides a foundation for innovative therapeutic interventions for both lymphoma and solid tumor malignancies.

The term "lectin" is derived from the Latin word lego- (aggregate) (Boyd & Shapleigh, 1954). Indeed, lectins' folds can flexibly alter their pocket structures just like Lego blocks, which enables them to grab a wide-variety of substances. Thus, this useful fold is well-conserved among various organisms. Through evolution, prototypic soluble lectins acquired transmembrane regions and signaling motifs to become C-type lectin receptors (CLRs). While CLRs seem to possess certain intrinsic affinity to self, some CLRs adapted to efficiently recognize glycoconjugates present in pathogens as pathogen-associated molecular patterns (PAMPs) and altered self. CLRs further extended their diversity to recognize non-glycosylated targets including pathogens and self-derived molecules. Thus, CLRs seem to have developed to monitor the internal/external stresses to maintain homeostasis by sensing various "unfamiliar" targets. In this review, we will summarize recent advances in our understanding of CLRs, their ligands and functions and discuss future perspectives.

The cGAS-STING pathway is responsible for cytoplasmic double-stranded DNA (dsDNA) -triggered innate immunity and involved in the pathology of various diseases including infection, autoimmune diseases, neurodegeneration and cancer. Understanding the activation and regulatory mechanisms of this pathway is critical to develop therapeutic strategies toward these diseases. Here, we review the signal transduction, cellular functions and regulations of cGAS and STING, particularly highlighting the latest understandings on the activation of cGAS by dsDNA and/or Manganese (Mn²⁺), STING trafficking, sulfated glycosaminoglycans (sGAGs)-induced STING polymerization and activation, and also regulation of the cGAS-STING pathway by different biocondensates formed via phase separation of proteins from host cells and viruses.

The discovery that B cells and αβ T cells exist was predictable: These cells gave themselves away through their products and biological effects. In contrast, there was no reason to anticipate the existence of γδ T cells. Even the accidental discovery of a novel TCR-like gene (later named γ) that did not encode TCR α or β proteins did not immediately change this. TCR-like γ had no obvious function, and its early expression in the thymus encouraged speculation about a possible role in αβ T cell development. However, the identification of human PBL-derived cell-lines which expressed CD3 in complex with the TCR-like γ protein, but not the αβ TCR, first indicated that a second T cell-type might exist, and the TCR-like γ chain was observed to co-precipitate with another protein. Amid speculation about a possible second TCR, this potential dimeric partner was named δ. To determine if the δ protein was indeed TCR-like, we undertook to sequence it. Meanwhile, a fourth TCR-like gene was discovered and provisionally named x. TCR-like x had revealed itself through genomic rearrangements early in T cell development, and was an attractive candidate for the gene encoding δ. The observation that δ protein sequences matched the predicted amino acid sequences encoded by the x gene, as well as serological cross-reactivity, confirmed that the TCR-like x gene indeed encoded the δ protein. Thus, the γδ heterodimer was established as a second TCR, and the cells that express it (the γδ T cells) consequently represented a third lymphocyte-population with the potential of recognizing diverse antigens. Soon, it became clear that γδ T cells are widely distributed and conserved among the vertebrate species, implying biological importance. Consistently, early functional studies revealed their roles in host resistance to pathogens, tissue repair, immune regulation, metabolism, organ physiology and more. Albeit discovered late, γδ T cells have repeatedly proven to play a distinct and often critical immunological role, and now generate much interest.

In some cases, antibodies can enhance virus entry and replication in cells. This phenomenon is called antibody-dependent infection enhancement (ADE). ADE not only promotes the virus to be recognized by the target cell and enters the target cell, but also affects the signal transmission in the target cell. Early formalin-inactivated virus vaccines such as aluminum adjuvants (RSV and measles) have been shown to induce ADE. Although there is no direct evidence that there is ADE in COVID-19, this potential risk is a huge challenge for prevention and vaccine development. This article focuses on the virus-induced ADE phenomenon and its molecular mechanism. It also summarizes various attempts in vaccine research and development to eliminate the ADE phenomenon, and proposes to avoid ADE in vaccine development from the perspective of antigens and adjuvants.

GFI1 and GFI1B are small nuclear proteins of 45 and 37kDa, respectively, that have a simple two-domain structure: The first consists of a group of six c-terminal C₂H₂ zinc finger motifs that are almost identical in sequence and bind to very similar, specific DNA sites. The second is an N-terminal 20 amino acid SNAG domain that can bind to the pocket of the histone demethylase KDM1A (LSD1) near its active site. When bound to DNA, both proteins act as bridging factors that bring LSD1 and associated proteins into the vicinity of methylated substrates, in particular histone H3 or TP53. GFI1 can also bring methyl transferases such as PRMT1 together with its substrates that include the DNA repair proteins MRE11 and 53BP1, thereby enabling their methylation and activation. While GFI1B is expressed almost exclusively in the erythroid and megakaryocytic lineage, GFI1 has clear biological roles in the development and differentiation of lymphoid and myeloid immune cells. GFI1 is required for lymphoid/myeloid and monocyte/granulocyte lineage decision as well as the correct nuclear interpretation of a number of important immune-signaling pathways that are initiated by NOTCH1, interleukins such as IL2, IL4, IL5 or IL7, by the pre TCR or -BCR receptors during early lymphoid differentiation or by T and B cell receptors during activation of lymphoid cells. Myeloid cells also depend on GFI1 at both stages of early differentiation as well as later stages in the process of activation of macrophages through Toll-like receptors in response to pathogen-associated molecular patterns. The knowledge gathered on these factors over the last decades puts GFI1 and GFI1B at the center of many biological processes that are critical for both the innate and acquired immune system.

Functionally competent and self-tolerant T cell repertoire is shaped through positive and negative selection in the cortical and medullary microenvironments of the thymus. The thymoproteasome specifically expressed in the cortical thymic epithelium is essential for the optimal generation of CD8⁺ T cells. Although how the thymoproteasome governs the generation of CD8⁺ T cells is not fully understood, accumulating evidence suggests that the thymoproteasome optimizes CD8⁺ T cell production through the processing of self-peptides associated with MHC class I molecules expressed by cortical thymic epithelial cells. In this review, we describe recent advances in the mechanism of thymoproteasome-dependent generation of CD8⁺ T cells, focusing on the process of cortical positive selection independent of apoptosis-mediated negative selection.