Nature Reviews Immunology最新文献

Interleukin-33 (IL-33) is an alarmin and cytokine that has potent biological effects in various tissues. It acts on a broad array of immune cell populations and is involved in many processes associated with health and disease. This Review discusses the biology of IL-33 and its receptor, ST2, and the functional relevance of IL-33-ST2 signalling. It focuses particularly on the differential regulation of IL-33 sensitivity in distinct cell types in diverse tissue settings. Furthermore, we describe the effects of IL-33 in various diseases, including viral infections, cancer, graft-versus-host disease, colitis, autoimmunity, chronic obstructive pulmonary disease, asthma and allergy. We also consider the roles of IL-33 in physiological reactions such as fat tissue biology and tissue regeneration. The Review aims to provide a comprehensive understanding of IL-33 signalling, including its potential as a target for developing new treatments, and to suggest future research directions.

Epigenetic regulation orchestrates B cell development, lineage commitment, subset differentiation and activation, and is equally central to the maintenance of B cell self-tolerance. Disruption of epigenetic homeostasis at successive tolerance checkpoints - from central tolerance in the bone marrow to peripheral tolerance at germinal centre and extrafollicular stages - can lead to the emergence of autoreactive B cells and the production of autoantibodies in systemic autoimmune diseases. In this Review, we describe the molecular mechanisms by which multiple epigenetic layers - encompassing DNA methylation, histone modification, chromatin remodelling, non-coding RNA regulation and RNA modification - collectively regulate normal B cell function and, when dysregulated, contribute to autoimmune pathogenesis. We examine how specific epigenetic axes, including microRNA-PI3K signalling, DNA demethylation-histone deacetylation balance and chromosome-linked innate immune receptor control, underpin tolerance checkpoint failure and B cell dysfunction in autoimmune disease. Finally, we discuss emerging epigenetic-targeted therapeutic strategies and highlight future research directions aimed at modulating disease-relevant B cell programmes in systemic autoimmunity.

Balanced activity of neuronal and immune networks is essential for maintaining central nervous system (CNS) function and mental health, whereas disturbances in network dynamics often lead to excitotoxicity and progressive pathology across brain diseases. Emerging evidence indicates that immune-mediated mechanisms can shape excitotoxic injury at least as profoundly as classical glutamatergic transmission. Here, we extend the concept of excitotoxicity beyond glutamate receptor overactivation to include innate and adaptive immune pathways, introducing the framework of immune-mediated excitotoxicity. We focus on three illustrative settings: epilepsy and ischaemic injury, where reiterative feedback between neuronal excitation and neuroimmune activation promotes acute excitotoxic damage; neurodegenerative disorders, in which misfolded protein aggregates act as immune stressors that amplify local inflammation; and multiple sclerosis, characterized by persistent, compartmentalized inflammation that drives chronic excitotoxic cycles. Across these examples, we define three hallmarks - feedback, stressor and chronicity - as organizing principles of this paradigm and describe the dynamic communication between neuronal and immune networks that underlies immune-mediated excitotoxicity. Recognizing these neuroimmune interactions as central to CNS homeostasis and - when perturbed - to disease opens up new avenues for therapeutic intervention targeting immune-mediated excitotoxicity.

Senescence, which is defined as a state of stable cell cycle arrest, can occur in all tissues of the body. The surveillance and clearance of senescent cells by the immune system is necessary for tissue homeostasis; when this immune surveillance does not occur efficiently, for example, during tumorigenesis and ageing, it has pathological consequences. For example, if the immune clearance of senescent cells is evaded, such as through recruitment of immunosuppressive cells, expression of immune checkpoint molecules by senescent cells or suppression of antigen presentation, senescent cells accumulate and lead to tissue dysfunction. Therefore, therapeutic modulation of the immune surveillance of senescent cells could be effective for the prevention and treatment of age-associated diseases including cancer. In this Review, we discuss our current understanding of the tissue-specific and context-specific processes that influence immune surveillance of senescent cells. We highlight the need for further research examining senescence across additional settings as well as the role of unexplored immune cell populations.

Ferroptosis is an iron-dependent form of regulated cell death driven by disrupted iron homeostasis and uncontrolled lipid peroxidation. Various metabolites and enzymes regulate cellular sensitivity to ferroptosis by affecting iron, lipid and redox metabolism. These pathways not only signal ferroptotic cell death but also affect the biology of T cells. The pathways include mechanisms by which iron metabolism regulates T cell activation via transferrin receptor 1-mTOR signalling, mechanisms by which lipid peroxidation drives vulnerability to ferroptosis in tumour-infiltrating CD8⁺ T cells, and mechanisms by which redox networks are balanced to maintain T cell survival. Here, we highlight the T cell subset-specific effects of ferroptosis-related pathways and ferroptosis susceptibility, and the implications for immunotherapy. We also discuss the emerging therapeutic strategies, including ferroptosis-resistant adoptive T cell therapy and ferroptosis-inducing approaches, that enhance the efficacy of immune checkpoint blockade for cancer treatment. Finally, we propose a framework for precision T cell-based immunotherapies, positioning ferroptosis as a tunable node linking T cell biology to clinical innovations.