Trends in Immunology最新文献

The NLRP3 inflammasome plays a central role in host defense against microbial infections but also contributes to inflammatory diseases. Functioning of NLRP3 strictly relies on two signals: a 'priming signal' that licenses NLRP3 activity and an 'activation signal' that triggers inflammasome assembly and downstream caspase-1 activation. The priming signal involves transcriptional upregulation of NLRP3 and diverse post-translational modifications that regulate its stability, subcellular localization, and protein-protein interactions. This multilayered regulation prevents untimely inflammasome activation while enabling its rapid assembly when both priming and activation signals are present. Here, we focus on the complexity of the priming signal and critically analyze and discuss how diverse post-translational modifications cooperate to prime NLRP3, controlling its activity in health and disease.

Germinal center B cell-like diffuse large B cell lymphoma (GCB-DLBCL) originates from the malignant transformation of germinal center B cells. This process is driven by transcriptional and epigenetic dysregulations, frequently caused by recurrent mutations and chromosomal translocations. These changes lead to a differentiation arrest associated with unchecked proliferation and survival. This review highlights key transcriptional and epigenetic dependencies that sustain the GCB-DLBCL phenotype and identifies therapeutic vulnerabilities. Epigenetic targeting of these vulnerabilities unlocks tumor cells from their differentiation arrest, enabling further yet incomplete differentiation toward an antiproliferative, proapoptotic plasma cell-like or memory B cell-like state. We define this transition as an epigenetically programmed identity crisis, a promising therapeutic strategy to target GCB-DLBCL and potentially other malignancies.

Trained immunity (TRIM) is a de facto form of innate immune memory. While histone modifications contribute to TRIM, their reversible nature and susceptibility to dilution during cell division cannot fully account for its long-term persistence. Here, we propose that DNA methylation patterns, particularly hypomethylation at proinflammatory gene loci, could serve as a key epigenetic mechanism contributing to long-term TRIM. Mechanistically, these hypomethylated states are biochemically stable and faithfully inherited through cell division, acting as a permissive scaffold that enables the rapid accumulation of activating histone marks upon restimulation. This DNA-methylation-mediated process could underpin the durability of TRIM across multiple contexts, including hematopoietic stem cell self-renewal, differentiation from central to peripheral compartments, and autonomy of tissue-resident cells.

Orthoflaviviruses - including dengue, Zika, yellow fever, Japanese encephalitis, and Powassan viruses - are mosquito- and tick-borne members of the family Flaviviridae. Orthoflaviviruses pose major public health threats, with the potential for epidemics and pandemics. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines offer a powerful platform by delivering in vitro-synthesized viral antigen-encoding mRNAs into the host, where they generate proteins that trigger robust immune responses. These synthetic platforms simplify the expression of complex viral glycoproteins, allow rapid and scalable manufacturing that is critical in a pandemic/epidemic scenario, and support multivalent designs to broaden protection. This review highlights recent advancements in mRNA vaccines for orthoflaviviruses and examines how innovations in antigen design and delivery platforms may offer broad, safe, and durable protection against diverse pathogenic orthoflaviviruses.

Despite an effective combination of antiretroviral therapy, HIV persists as a lifelong infection and global health threat. The human host equips restriction factors and interferon (IFN)-stimulated genes that target every step of the viral life cycle. However, HIV-1 has evolved a coordinated immune evasion strategy using a limited set of accessory proteins with distinct antagonistic functions. This functional division of labor allows HIV-1 to disable key immune pathways and ensure persistence. Here, we explore the molecular interplay between host defenses and HIV-1, organizing antiviral factors by viral life cycle stage. We further reframe viral immune evasion as a strategic division of labor among accessory proteins each adapted to target specific host defenses, offering insights for next-generation therapies.

Immune activity at the cerebrospinal fluid (CSF)-dura-brain interface regulates key functions of brain physiology. In two back-to-back papers, Mamuladze et al. and Kothari et al. show that dural mast cells (MCs) are strategically positioned to coordinate this regulation, controlling CSF flow dynamics and immune cell trafficking in allergy, meningitis, and stroke.

Autoimmune diseases arise from genetic and environmental factors that disrupt immune tolerance. Recent studies highlight the role of myeloid cell immunometabolism, particularly mitochondrial dysfunction, in driving autoimmunity. Mitochondria regulate energy homeostasis and cell fate; their impairment leads to defective immune cell differentiation, abnormal effector activity, and chronic inflammation. We propose that chronic metabolic stress reprograms myeloid cells, fueling a vicious cycle of cell death and immune activation. Over time, this may induce several states of maladaptation in myeloid cells. Viewing autoimmune disease through a metabolic lens offers new insight into disease mechanisms and highlights potential therapeutic opportunities targeting mitochondrial function to restore immune balance.

The complement genes harbour genetic variants that affect numerous diseases; however, these genes are notoriously repeat-heavy, and these repeat regions are largely unexplored for disease-relevant genetic variation. Elucidating these 'dark' regions is now possible using long-read sequencing (LRS), enabling identification of novel disease-relevant genetic variants.

Recently, a large pool of antigens derived from viral and bacterial microorganisms showing molecular mimicry with tumour-cell-expressed antigens was identified. These antigens can be presented by MHC molecules and elicit T cells that are crossreactive with microbial antigens and tumour-cell-associated antigens. In the setting of metastatic melanoma, such T cells can contribute to the response induced by immune checkpoint blockade therapy. Here, the current understanding of molecular mimicry in T cell-mediated tumour immunity and how this might be exploited for developing new preventive and therapeutic approaches for cancer is described. In particular, the literature on the concept and evidence of molecular mimicry in cancer is reviewed, covering the whole translational spectrum, from the antigen discovery strategy to the clinical evaluation.

Intrahepatic immune responses are often insufficient to control hepatitis virus infections. A recent study by Venzin and colleagues demonstrates a detailed mechanism by which an intrahepatic tricellular network and the cytokine IL-27 can augment virus-specific immunity.