Trends in Immunology最新文献

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.

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.

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.

Cholesterol metabolites, particularly oxidized forms known as oxysterols, play crucial roles in modulating immune and metabolic processes across various tissues. Concentrations of local cholesterol and its metabolites influence tissue-specific immune responses by shaping the metabolic and spatial organization of immune cells in barrier organs like the small intestine (SI) and lungs. We explore recent molecular and cellular evidence supporting the metabolic adaptation of innate and adaptive immune cells in the SI and lung, driven by cholesterol and cholesterol metabolites. Further research should unravel the detailed molecular mechanisms and spatiotemporal adaptations involving cholesterol metabolites in distinct mucosal tissues in homeostasis or infection. We posit that pharmacological interventions targeting the generation or sensing of cholesterol metabolites might be leveraged to enhance long-term immune protection in mucosal tissues or prevent autoinflammatory states.

The respiratory tract is exposed to infection from inhaled pathogens, including viruses, bacteria, and fungi. So far, a comprehensive assessment that integrates common and distinct aspects of the immune response along different areas of the respiratory tract has been lacking. Here, we discuss key recent findings regarding anatomical, functional, and microbial factors driving regional immune adaptation in the mammalian respiratory system, how they differ between mice and humans, and the similarities and differences with the gastrointestinal tract. We demonstrate that, under evolutionary pressure, mammals evolved spatially organized immune defenses that vary between the upper and lower respiratory tract. Overall, we propose that the functional specialization of the immune response along the respiratory tract has fundamental implications for the management of infectious or inflammatory diseases.

Brain metastasis poses formidable clinical challenges due to its intricate interactions with the brain's unique immune environment, often resulting in poor prognoses. This review delves into systems immunology's role in uncovering the dynamic interplay between metastatic cancer cells and brain immunity. Leveraging spatial and single-cell technologies, along with advanced computational modeling, systems immunology offers unprecedented insights into mechanisms of immune evasion and tumor proliferation. Recent studies highlight potential immunotherapeutic targets, suggesting strategies to boost antitumor immunity and counteract cancer cell evasion in the brain. Despite substantial progress, challenges persist, particularly in accurately simulating human conditions. This review underscores the need for interdisciplinary collaboration to harness systems immunology's full potential, aiming to dramatically improve outcomes for patients with brain metastasis.

Gao, Kim, and colleagues recently reported that clonal populations of CD4⁺ T cells could be detected in mice that underwent spinal cord injury (SCI). A subset of clones mediated enhanced motor recovery and suppressed inflammation. Further studies may point towards novel cell therapies for SCI, for which care is presently supportive only.

The development of mammalian adaptive (i.e., B and T cell-mediated) immune responses is tightly controlled at transcriptional, epigenetic, and metabolic levels. Signals derived from the extracellular milieu are crucial regulators of adaptive immunity. Beyond the traditionally studied cytokines and chemokines, many other extracellular metabolites can bind to specialized receptors and regulate T and B cell immune responses. These molecules often accumulate extracellularly through active export by plasma membrane transporters. For example, mammalian immune and non-immune cells express pannexin (PANX)1-3 channels on the plasma membrane, which release many distinct small molecules, notably intracellular ATP. Here, we review novel findings defining PANXs as crucial regulators of T and B cell immune responses in disease contexts such as cancer or viral infections.

Immune cell fate decisions are regulated, at least in part, by nuclear architecture. Here, we outline how nuclear architecture instructs mammalian polymorphonuclear cell differentiation. We discuss how in neutrophils loop extrusion mechanisms regulate the expression of genes involved in phagocytosis and shape nuclear morphology. We propose that diminished loop extrusion programs also orchestrate eosinophil and basophil differentiation. We portray a new model in which competitive physical forces, loop extrusion, and phase separation, instruct mononuclear versus polymorphonuclear cell fate decisions. We posit that loop extrusion programs instruct the spatial organization of cytoplasmic organelles, including neutrophil granules, mitochondria, and endoplasmic reticulum. Finally, we suggest that changing loop extrusion programs might allow the engineering of new nuclear shapes and artificial cytoplasmic architectures.