Trends in Immunology最新文献

The brain is no longer viewed as immunologically isolated but as an organ surrounded by dynamic border compartments that coordinate surveillance, drainage, and communication with the periphery. Key interfaces - including the meninges, blood-brain barrier, choroid plexus (ChP), and skull bone marrow - host specialized immune niches that regulate antigen sampling, leukocyte trafficking, and neuroimmune signaling. Recent advances in imaging and in single-cell and spatial profiling have revealed previously unrecognized cell types, migration routes, and barrier specializations that shape central nervous system (CNS) immunity in health and disease. Understanding how these border tissues sense, integrate, and modulate immune activity opens opportunities for therapeutically tuning neuroimmune responses at the brain's periphery while preserving parenchymal integrity.

Bidirectional crosstalk between the immune and nervous systems, via 'neuroimmune circuits', regulates homeostatic and inflammatory responses essential for health. Microglia, long-lived brain macrophages, act as key hubs integrating immune signals into coordinated brain responses by shifting into distinct functional states in response to local and systemic cues. In this review, we focus on how environmental signals shape these microglial states, how microglia influence other brain cells through both direct and indirect mechanisms, and emerging evidence of how microglia are impacted by, and respond to, peripheral changes. We highlight microglia as central players in systemic neuroimmune communication, influencing both brain and peripheral health, while outlining recent tools and key knowledge gaps to guide future research into mechanisms of neuroimmune circuit communication.

Insights into T-cell biology in the central nervous system (CNS) have evolved from early neuroinflammatory models demonstrating the pathogenic potential of autoreactive T cells to recent human studies defining resident T-cell populations in the healthy and diseased brain. We here discuss advances in postmortem brain tissue processing, flow cytometry, and transcriptional profiling revealing that human brain CD8⁺ and CD4⁺ T cells are tissue-resident memory T cells with distinct phenotypes shaped by CNS borders and parenchymal niches. These findings refine our understanding of CNS immune surveillance and provide a framework for dissecting T-cell contributions to multiple sclerosis.

Regulatory T cells (T_regs) have gained renewed attention for their diverse roles beyond immune suppression. This review integrates recent discoveries on how tissue-resident T_regs integrate immune, metabolic, and neural cues to maintain organ homeostasis and regeneration. Across adipose tissue, intestine, brain, and skin, T_regs coordinate local networks that couple immune tolerance with metabolic balance and tissue repair. We further discuss therapeutic advances - including antigen-specific chimeric antigen receptor (CAR)/T cell receptor (TCR) T_regs, interleukin 2 (IL-2) muteins, and metabolic modulation - that aim to harness T_regs for treating autoimmunity and chronic inflammation. Together, these insights highlight T_regs as central interpreters of tissue context and as promising targets for next-generation precision immunotherapy.

Interleukin-23 (IL-23) is a pleiotropic cytokine that maintains the delicate balance between tolerance to commensal microbiota and defense against pathogens at mucosal barriers. When dysregulated, IL-23 becomes a key driver of chronic inflammation, with therapeutics blocking this pathway being successfully harnessed in the clinic. In this review, we discuss recently uncovered biology of IL-23 in the context of mucosal immunity, which intimately links the role of this pathway to the pathophysiology of autoimmunity, chronic inflammation, and emerging functions in cancer. Through the lens of the cell types that respond to IL-23, the engaged effector programs, and the key functions in health and disease, we highlight recent advances and opportunities to better understand the dichotomous outcomes mediated by this cytokine.

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.

Salmonella enterica serovar Typhimurium (STm) represents a major global health burden. Strains endemic in sub-Saharan Africa cause life-threatening invasive non-typhoidal salmonellosis (iNTS) in vulnerable populations. Studies in the iNTS-like mouse model show that STm induces profound germinal centre (GC) disruption, impairing high-affinity, long-lived antibody and memory B cell formation - affecting nascent and pre-existing GC reactions. Lipopolysaccharide (LPS) and specific STm type 3 secretion effectors drive GC collapse, but the determining bacteria-host interactions are still unclear. Although STm induces an extrafollicular (EF) B cell response generating protective antibodies, their longevity remains unclear. With no licensed human vaccine for iNTS, we propose that vaccine strategies should consider ways to protect GC integrity and include GC parameters as endpoints in preclinical trials.

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.

Inflammasomes have emerged as central regulators of (auto)immune pathology, including multiple sclerosis (MS). Once exclusively considered in the domain of myeloid cells, both canonical and noncanonical inflammasomes are now recognized in diverse immune and nonimmune populations relevant to MS, including T lymphocytes, blood-brain barrier (BBB) endothelial cells (EnC), and oligodendrocytes (ODCs). Elevated inflammasome activity is evident in patient-derived samples, particularly within active brain lesions. Experimental autoimmune encephalomyelitis (EAE) models confirm the pathogenic contribution of inflammasomes, as genetic deletion or pharmacological inhibition of inflammasomes mitigate disease. These advances position inflammasomes at the intersection of neuroinflammation and neurodegeneration, and highlight inflammasome inhibition as a promising therapeutic avenue currently under investigation in preclinical and early clinical studies.

Parity and lactation have long been recognised as protective factors in breast cancer, with notable risk reduction in triple negative breast cancer (TNBC). Recent work by Virassamy et al. suggests a tissue-specific, persistent immune surveillance underpins this effect, particularly in women who have also breastfed.