Advances in Immunology最新文献

Autophagy, a highly conserved catabolic process that targets various types of cellular cargoes to lysosomal degradation, is one of the most important biological mechanisms critical for cellular homeostasis. Components of these cellular cargoes can range from individual proteins to invading pathogens, and degrading these materials is important for maintaining organismal health and survival. The process of autophagy is carried out by complex molecular mechanisms, and a growing body of evidence indicates that these mechanisms intersect with those involved in the cell death pathways. In this review, we examine several emerging studies elucidating the role of autophagy in RIP1-mediated cell death signaling, with particular emphasis on impaired autophagy caused by ATG16L1 deficiency. We also discuss how autophagy in RIP1-mediated cell death affects intestinal homeostasis in preclinical models, and the implications of the intersection between RIP1 and autophagy for understanding the intestinal pathologies associated with inflammatory bowel disease (IBD). Finally, we highlight the potential benefits of therapeutic targeting of RIP1 and autophagy proteins, while also proposing areas of research that will likely elucidate new links between autophagy and cell death signaling.

Interferon regulatory factor-8 (IRF8) is the lineage determining transcription factor for the type one classical dendritic cell (cDC1) subset, a terminal selector for plasmacytoid dendritic cells and important for the function of monocytes. Studies of Irf8 gene regulation have identified several enhancers controlling its activity during development of progenitors in the bone marrow that precisely regulate expression at distinct developmental stages. Each enhancer responds to distinct transcription factors that are expressed at each stage. IRF8 is first expressed in early progenitors that form the monocyte dendritic cell progenitor (MDP) in response to induction of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) acting at the Irf8 +56 kb enhancer. IRF8 levels increase further as the MDP transits into the common dendritic cell progenitor (CDP) in response to E protein activity at the Irf8 +41 kb enhancer. Upon Nfil3-induction in CDPs leading to specification of the cDC1 progenitor, abrupt induction of BATF3 forms the JUN/BATF3/IRF8 heterotrimer that activates the Irf8 +32 kb enhancer that sustains Irf8 autoactivation throughout the cDC1 lifetime. Deletions of each of these enhancers has revealed their stage dependent activation. Surprisingly, studies of compound heterozygotes for each combination of enhancer deletions revealed that activation of each subsequent enhancer requires the successful activation of the previous enhancer in strictly cis-dependent mechanism. Successful progression of enhancer activation is finely tuned to alter the functional accessibility of subsequent enhancers to factors active in the next stage of development. The molecular basis for these phenomenon is still obscure but could have implications for genomic regulation in a broader developmental context.

Spontaneously formed germinal centers (GCs) have been reported in most mouse models of human autoimmune disease and autoimmune patients, and have long been considered a source of somatically-mutated and thus high affinity autoantibodies, but their role in autoimmunity is becoming increasingly controversial, particularly in the context of systemic autoimmune diseases like lupus. On the one hand, there is good evidence that some pathogenic lupus antibodies have acquired somatic mutations that increase affinity for self-antigens. On the other hand, recent studies that have genetically prevented GC formation, suggest that GCs are dispensable for systemic autoimmunity, pointing instead to pathogenic extrafollicular (EF) B-cell responses. Furthermore, several lines of evidence suggest germinal centers may in fact be somewhat protective in the context of autoimmunity. Here we review how some of the conflicting evidence arose, and current views on the role of GCs in autoimmunity, outlining mechanisms by which GC may eliminate self-reactivity. We also discuss recent advances in understanding extrafollicular B cell subsets that participate in autoimmunity.

As potent pro-inflammatory mediators, IL-17 family cytokines play crucial roles in the pathogenesis of various inflammatory and autoimmune skin disorders. Although substantial progress has been achieved in understanding the pivotal role of IL-17A signaling in psoriasis, leading to the development of highly effective biologics, the functions of other IL-17 family members in inflammatory or autoimmune skin diseases remain less explored. In this review, we provide a comprehensive overview of IL-17 family cytokines and their receptors, with a particular focus on the recent advancements in identifying cellular sources, receptors and signaling pathways regulated by these cytokines. At the end, we discuss how the aberrant functions of IL-17 family cytokines contribute to the pathogenesis of diverse inflammatory or autoimmune skin diseases.

The emergence and re-emergence of infectious diseases present significant global health threats. Understanding their pathogenesis is crucial for developing diagnostics, therapeutics, and preventive strategies. System-level integrative omics analysis offers a comprehensive approach to deciphering virus-host immunometabolic interactions during infections. Multi-omics approaches, integrating genomics, transcriptomics, proteomics, and metabolomics, provide holistic insights into disease mechanisms, host-pathogen interactions, and immune responses. The interplay between the immune system and metabolic processes, termed immunometabolism, has gained attention, particularly in infectious diseases. Immunometabolic studies reveal how metabolic processes regulate immune cell function, shaping immune responses and influencing infection outcomes. Metabolic reprogramming is crucial for immune cell activation, differentiation, and function. Using systems biological algorithms to understand the immunometabolic alterations can provide a holistic view of immune and metabolic pathway interactions, identifying regulatory nodes and predicting responses to perturbations. Understanding these pathways enhances the knowledge of immune regulation and offers avenues for therapeutic interventions. This review highlights the contributions of multi-omics systems biology studies in understanding infectious disease pathogenesis, focusing on RNA viruses. The integrative approach enables personalized medicine strategies, considering individual metabolic and immune variations. Leveraging these interdisciplinary approaches promises advancements in combating RNA virus infections and improving health outcomes, highlighting the transformative impact of multi-omics technologies in infectious disease research.

Activation induced cytidine deaminase (AID) is a key element of the adaptive immune system, required for immunoglobulin isotype switching and affinity maturation of B-cells as they undergo the germinal center (GC) reaction in peripheral lymphoid tissue. The inherent DNA damaging activity of this enzyme can also have off-target effects in B-cells, producing lymphomagenic chromosomal translocations that are characteristic features of various classes of non-Hodgkin B-cell lymphoma (B-NHL), and generating oncogenic mutations, so-called aberrant somatic hypermutation (aSHM). Additionally, AID has been found to affect gene expression through demethylation as well as altered interactions between gene regulatory elements. These changes have been most thoroughly studied in B-NHL arising from GC B-cells. Here, we describe the most common classes of GC-derived B-NHL and explore the consequences of on- and off-target AID activity in B and plasma cell neoplasms. The relationships between AID expression, including effects of infection and other exposures/agents, mutagenic activity and lymphoma biology are also discussed.

The role of aberrantly expressed proteins in tumors in driving immune-mediated control of cancer has been well documented for more than five decades. Today, we know that both aberrantly expressed normal proteins as well as mutant proteins (neoantigens) can function as tumor antigens in both humans and mice. Next-generation sequencing (NGS) and high-resolution mass spectrometry (MS) technologies have made significant advances since the early 2010s, enabling detection of rare but clinically relevant neoantigens recognized by T cells. MS profiling of tumor-specific immunopeptidomes remains the most direct method to identify mutant peptides bound to cellular MHC. However, the need for use of large numbers of cells or significant amounts of tumor tissue to achieve neoantigen detection has historically limited the application of MS. Newer, more sensitive MS technologies have recently demonstrated the capacities to detect neoantigens from fewer cells. Here, we highlight recent advancements in immunopeptidomics-based characterization of tumor-specific neoantigens. Various tumor antigen categories and neoantigen identification approaches are also discussed. Furthermore, we summarize recent reports that achieved successful tumor neoantigen detection by MS using a variety of starting materials, MS acquisition modes, and novel ion mobility devices.

In this review we discuss an underexposed mechanism in the adaptive immune system where B cell and T cell immunity collaborate. The main function of B cell immunity is the generation of antibodies which are well known for their high affinity and antigen-specificity. Antibodies can bind antigens in soluble form making so-called immune complexes (ICs) or can opsonize antigen-exposing cells or particles for degradation. This leads to well-known effector mechanisms complement activation, antibody-dependent cytotoxicity and phagocytosis. What is less realized is that antibodies can play an important role in the targeting of antigen to dendritic cells (DCs) and thereby can drive T cell immunity. Here we summarize the studies that described this highly efficient process of antibody-mediated antigen uptake in DCs in vitro and in vivo. Only very low doses of antigen can be captured by circulating antibodies and subsequently trapped by DCs in vivo. We studied the handling of these ICs by DCs in subcellular detail. Upon immune complex engulfment DCs can sustain MHC class I and II antigen presentation for many days. Cell biological analysis showed that this function is causally related to intracellular antigen-storage compartments which are functional endolysosomal organelles present in DCs. We speculate that this function is immunologically very important as DCs require time to migrate from the site of infection to the draining lymph nodes to activate T cells. The implications of these findings and the consequences for the immune system, immunotherapy with tumor-specific antibodies and novel vaccination strategies are discussed.

The immune system is deeply involved in autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis, N-methyl-d-aspartate (NMDA) receptor encephalitis, and narcolepsy. Additionally, the immune system is involved in various brain diseases including cerebral infarction and neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). In particular, reports related to T cells are increasing. T cells may also play important roles in brain deterioration and dementia that occur with aging. Our understanding of the role of immune cells in the context of the brain has been greatly improved by the use of acute ischemic brain injury models. Additionally, similar neural damage and repair events are shown to occur in more chronic brain neurodegenerative brain diseases. In this review, we focus on the role of T cells, including CD4⁺ T cells, CD8⁺ T cells and regulatory T cells (Tregs) in cerebral infarction and neurodegenerative diseases.

The biggest challenge to immune control of HIV infection is the rapid within-host viral evolution, which allows selection of viral variants that escape from T cell and antibody recognition. Thus, it is impossible to clear HIV infection without targeting "immutable" components of the virus. Unlike the adaptive immune system that recognizes cognate epitopes, the CARD8 inflammasome senses the essential enzymatic activity of the HIV-1 protease, which is immutable for the virus. Hence, all subtypes of HIV clinical isolates can be recognized by CARD8. In HIV-infected cells, the viral protease is expressed as a subunit of the viral Gag-Pol polyprotein and remains functionally inactive prior to viral budding. A class of anti-HIV drugs, the non-nucleoside reverse transcriptase inhibitors (NNRTIs), can promote Gag-pol dimerization and subsequent premature intracellular activation of the viral protease. NNRTI treatment triggers CARD8 inflammasome activation, which leads to pyroptosis of HIV-infected CD4⁺ T cells and macrophages. Targeting the CARD8 inflammasome can be a potent and broadly effective strategy for HIV eradication.