Trends in Immunology最新文献

The polycomb repressive complex 2 (PRC2) is an established therapeutic target in cancer. PRC2 catalyzes methylation of histone H3 at lysine 27 (H3K27me3) and is known for maintaining eukaryote cell identity. Recent discoveries show that modulation of PRC2 not only impacts cell differentiation and tumor growth but also has immunomodulatory properties. Here, we integrate multiple immunological fields to understand PRC2 and its subunits in epigenetic canonical regulation and non-canonical mechanisms within innate immunity. We discuss how PRC2 regulates hematopoietic stem cell proliferation, myeloid cell differentiation, and shapes innate immune responses. The PRC2 catalytic domain EZH2 is upregulated in various human inflammatory diseases and its deletion or inhibition in experimental mouse models can reduce disease severity, emphasizing its importance in regulating inflammation.

Effector-triggered immunity (ETI) enables hosts to react to pathogens by monitoring few key cellular processes. ETI responses are assumed to be similar toward related pathogen effectors. However, recent evidence from the invertebrate model Caenorhabditis elegans and pore-forming toxins indicates a much more complex and specific ETI than previously anticipated.

Men are at higher risk for developing severe COVID-19 than women, while women are at higher risk for developing post-acute sequelae of COVID-19 (PASC). This highlights the impact of sex differences on immune responses and clinical outcomes of acute COVID-19 or PASC. A dynamic immune-endocrine interface plays an important role in the development of effective immune responses impacting the control of viral infections. In this opinion article we discuss mechanisms underlying the transcriptional and epigenetic regulation of immune responses by sex hormones during viral infections. We propose that disruption of this delicate immune-endocrine interplay can result in worsened outcomes of viral disease. We also posit that insights into these immune mechanisms can propel the development of novel immunomodulatory interventions that leverage immune-endocrine pathways to treat viral infections.

While primarily a sensory organ, the mammalian olfactory epithelium (OE) also plays a critical role as an immune barrier. Mechanisms governing interactions between the immune system and this specialized chemosensory tissue are gaining interest, in part sparked by the COVID-19 pandemic. Regulated inflammation is intrinsic to normal mucosal healing and homeostasis, but prolonged OE inflammation is associated with persistent loss of smell, belying the intertwining of local mucosal immunology and olfactory function. Evidence supports bidirectional communication between OE cells and the immune system in health and disease. Recent investigations suggest that neuro-immune cross-talk modulates olfactory stem cell behavior and neuronal regeneration dynamics, prioritizing the epithelial-like non-neuronal framework with immune barrier function at the expense of the neurosensory organ in chronic inflammation.

Innate immune cells that are epigenetically reprogrammed by infection can modify host responses to subsequent infections. Lercher et al. have identified epigenetic reprogramming of murine airway-resident macrophages following recovery from SARS-CoV-2 infection, conferring protection from pathology and lethality following secondary influenza A virus (IAV) challenge without reducing viral titers.

Solute carrier proteins (SLCs) are pivotal for maintaining cellular homeostasis by transporting small molecules across cellular membranes. Recent discoveries have uncovered their involvement in modulating innate immunity, particularly within the cytosol. We review emerging evidence that links SLC transporters to cytosolic innate immune recognition and highlight their role in regulating inflammation. We explore how SLC transporters influence the activation of endosomal Toll-like receptors, cytosolic NODs, and STING sensors. Understanding the contribution of SLCs to innate immune recognition provides insight into their fundamental biological functions and opens new avenues to develop possible therapeutic interventions for autoimmune and inflammatory diseases. This review aims to discuss current knowledge and identify key gaps in this rapidly evolving field.

Following on from the discovery that innate immune pathways are shared widely across the tree of life comes another surprise: Hobbs et al. show that viruses targeting animals and bacteria also use highly conserved tools to fight back. Why such mechanisms remain seemingly unchanged despite the rapid coevolution among hosts and pathogens is now a key open question for the field.

Peripheral immune cells play an important role in the pathology of Alzheimer's disease (AD), impacting processes such as amyloid and tau protein aggregation, glial activation, neuronal integrity, and cognitive decline. Here, we examine cutting-edge strategies - encompassing animal and cellular models - used to investigate the roles of peripheral immune cells in AD. Approaches such as antibody-mediated depletion, genetic ablation, and bone marrow chimeras in mouse models have been instrumental in uncovering T, B, and innate immune cell disease-modifying functions. However, challenges such as specificity, off-target effects, and differences between human and mouse immune systems underscore the need for more human-relevant models. Emerging multicellular models replicating critical aspects of human brain tissue and neuroimmune interactions increasingly offer fresh insights into the role of immune cells in AD pathogenesis. Refining these methodologies can deepen our understanding of immune cell contributions to AD and support the development of novel immune-related therapeutic interventions.

Combinations of the highly polymorphic KIR and HLA-I genes are associated with numerous human diseases. Interpreting these associations requires a molecular understanding of the multiple killer-cell immunoglobulin-like receptor (KIR)-human leukocyte antigen-1 (HLA-I) receptor-ligand interactions on natural killer (NK) cells and identifying the salient features that underlie disease risk. We hypothesize that a critical discriminating factor in KIR-HLA-I interactions is the selective detection of HLA-I-bound peptides by KIRs. We propose a 'peptide selectivity model', where high-avidity KIR-HLA-I interactions reflect low selectivity for peptides conferring consistent NK cell inhibition across different tissue immunopeptidomes. Conversely, lower-avidity interactions (including those with activating KIRs) are more dependent on HLA-I-bound peptide sequence, requiring an appreciation of how HLA-I immunopeptidomes influence KIR binding and regulate NK cell function. Relevant to understanding NK cell function and pathology, we interpret known KIR-HLA-I combinations and their associations with certain human diseases in the context of this 'peptide selectivity model'.

Tissue-resident memory (T_RM) T cells not only control infection and cancer, but also contribute to inflammatory disease. In a recent study, Obers et al. demonstrate that retinoic acid (RA) and TGF-β direct T_RM residency in mice, with RA uniquely retaining cells in the intestine by limiting migration. This discovery highlights the potential for harnessing local residency cues to enhance tissue-specific T_RM responses.