Immunological Reviews最新文献

Type 2 immunity represents a unique immune module that provides host protection against macro-parasites and noxious agents such as venoms and toxins. In contrast, maladaptive type 2 immune responses cause allergic diseases. While multiple cell types play important roles in type 2 immunity, recent studies in humans and murine models of chronic allergic diseases have shown that a distinct population of tissue-resident, CD4+ T helper type 2 (Th2) cells play a critical role in chronic allergic inflammation. The rules regulating Th2 cell differentiation have remained less well defined than other T cell subsets, but recent studies have shed new light into the specific mechanisms controlling Th2 cell biology in vivo. Here, we review our current understanding of the checkpoints regulating the development and function of tissue-resident Th2 cells with a focus on chronic allergic diseases. We discuss evidence for a barrier tissue checkpoint in initial Th2 cell priming, including the role of neuropeptides, damage-associated molecular patterns, and dendritic cell macro-clusters. Furthermore, we review the evidence for a second barrier tissue checkpoint that instructs the development of multi-cytokine producing, tissue-resident Th2 cells that orchestrate allergic inflammation. Lastly, we discuss potential approaches to therapeutically target tissue-resident Th2 cells in chronic allergic diseases.

The immune system relies on carefully calibrated cellular machineries to enable distinction between endogenous and foreign molecules, with autoimmunity arising when this balance is disrupted. As potent autoantibody factories, B cells are major drivers of many autoimmune diseases. A significant fraction of patients affected by chronic autoimmune diseases such as systemic lupus erythematosus (SLE) exhibit pathogenic accumulation of B-cell subsets that are believed to be derived from the extrafollicular (EF) differentiation pathway. These B-cell subsets, although variously named and exhibiting intrinsic heterogeneity, are all poised producers of autoantibodies that correlate with patient pathophysiology. In addition, they are often characterized by biomarkers known to drive the innate immune response, including toll-like receptors and complement receptors. Although many innate receptors have well-established functions in myeloid cells and other immune cell types, their B cell-specific functions are still under active investigation and are crucial for understanding the molecular pathways that drive B-cell breaks of tolerance. In this review, we summarize studies on innate immune receptors that serve prominent roles in regulating EF B-cell activation in health and autoimmunity. By discussing independent and collaborative functions of these receptors, we hope to provide new perspectives in autoimmune disease signature research.

The genome-based surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the past nearly 5 years since its emergence has refreshed our understanding of virus evolution, especially on convergent co-evolution with the host. SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations that affect the functional properties of the virus by altering its infectivity, virulence, transmissibility, and interactions with host immunity. This poses a huge challenge to global prevention and control measures based on drug treatment and vaccine application. As one of the key evasion strategies in response to the immune profile of the human population, there are overwhelming amounts of evidence for the reduced antibody neutralization of SARS-CoV-2 variants. Additionally, data also suggest that the levels of CD4⁺ and CD8⁺ T-cell responses against variants or sub-variants decrease in the populations, although non-negligible cross-T-cell responses are maintained. Herein, from the perspectives of structural immunology, we outline the characteristics and mechanisms of the T cell and antibody responses to SARS-CoV and its variants/sub-variants. The molecular bases for the impact of the immune escaping variants on the interaction of the epitopes with the key receptors in adaptive immunity, that is, major histocompatibility complex (MHC), T-cell receptor (TCR), and antibody are summarized and discussed, the knowledge of which will widen our understanding of this pandemic-threatening virus and assist the preparedness for Pathogen X in the future.

Respiratory viruses, including SARS-CoV-2, influenza, parainfluenza, rhinovirus, and respiratory syncytial virus (RSV), are pathogens responsible for lower respiratory tract infections, particularly in vulnerable populations such as children and the elderly. Upon infection, these viruses are recognized by pattern recognition receptors, leading to the activation of inflammasomes, which are essential for mediating inflammatory responses. This review discusses the mechanisms by which these RNA respiratory viruses activate inflammasomes, emphasizing the roles of various signaling pathways and components involved in this process. Additionally, we highlight the specific interactions between viral proteins and inflammasome sensors, elucidating how these viruses manipulate the host immune response to facilitate infection. Understanding the dynamics of inflammasome activation in response to respiratory viruses provides critical insights for developing immunomodulatory therapeutic strategies aimed at mitigating inflammation and improving outcomes in respiratory tract infections.

The immune checkpoint receptor lymphocyte activation gene-3 (LAG3) inhibits T-cell activation and was recently validated as a target for cancer immunotherapy. Despite its emergence as a therapeutic target, a lack of molecular-level insight has obscured our understanding of the LAG3 immunosuppression mechanism. This review highlights a series of breakthroughs that have illuminated fundamental aspects of LAG3 molecular biology. Key discoveries include structural insights into LAG3 interactions with ligands and antibodies, mechanistic studies of LAG3 interference with T-cell receptor (TCR) signaling, and the development of novel therapeutics. A particular focus is placed on structure–function relationships for LAG3-targeting drugs, as it has become apparent that several distinct approaches to LAG3 antagonism are viable. In addition to LAG3 antagonists, agonistic LAG3 antibodies and immunostimulatory LAG3 extracellular domains (ECDs) are discussed in the context of current structural and mechanistic data. Collectively, these findings should provide an updated landscape for the design of optimal LAG3-based therapeutics for cancer and autoimmune diseases.