Journal of Experimental Medicine最新文献

Central tolerance, which relies on the presentation of self-antigens by mTECs and DCs, prevents autoimmunity by eliminating self-reactive T cells. While mTECs produce self-antigens autonomously, DCs acquire them from mTECs via cooperative antigen transfer (CAT). We previously showed that mTEC and DC subsets exhibit preferential pairing in CAT, providing a rationale for the existence of molecular determinants underpinning this pairing and its outcome. Here, we compared the transcriptomes of CAT-experienced and CAT-inexperienced DCs and identified Claudin 1 as a molecule involved in CAT and type 1 DC (DC1) maturation. DC1-specific ablation of Claudin 1 resulted in decreased CAT to late mature DC1s and dramatically diminished DC1 maturation. These phenotypes correlated with the displacement of DC1s from mTECs and their decreased expression of MHCII pathway genes. This translated into impaired Treg selection and clonal deletion, ultimately manifesting in symptoms of multiorgan autoimmunity and shortened lifespan. Collectively, our results identify thymic DC1-derived Claudin 1 as a regulator of immune tolerance.

Runt-related transcription (RUNX) factors play a key role in T cell development. At the T-lineage commitment checkpoint, RUNX1 undergoes dynamic partner switching, resulting in its redeployment. Here, we investigated the functional differences in RUNX factors between the lymphoid progenitor (LP)- and Notch-stimulated earliest T progenitor stages (Phase 1). We identified CCCTC-binding factor (CTCF) as an LP-specific RUNX1-interacting partner, with LP-specific RUNX1-binding genomic sites significantly enriched for CTCF consensus motifs and co-occupied by CTCF. On Notch stimulation, Notch1 intracellular domain directly interacts with RUNX1 and recruits the RUNX1/Mediator/p300 transcriptional activation complex to Notch-regulated T-signature gene loci. CRISPR/Cas9-mediated stage-specific deletion of RUNX factors and their binding partners revealed that the RUNX1/CTCF complex in LP negatively regulates T-signature gene expression, whereas the RUNX1/Mediator/p300 complex in Phase 1 promotes it. Our findings highlight the crucial role of Notch-mediated functional conversion of RUNX factors, including protein complex reorganization and genomic redeployment in initiating T-lineage program.

Paneth cells secrete antimicrobial peptides (AMPs) to modulate composition of gut microbiota and host defense. AMPs are typically packaged into dense core vesicles (DCVs) and secreted into the intestinal lumen. However, the mechanisms underlying DCV biogenesis and secretion are still elusive. Here we identified that ERAdP was highly expressed in Paneth cells that acted as a sensor for a bacterial second messenger c-di-AMP. ERAdP deficiency caused impaired DCV biogenesis and dysfunction of Paneth cells. Mechanistically, by sensing c-di-AMP, ERAdP interacted with NLRP6 and further recruited ANXA2 onto the DCV membrane in Paneth cells. The ERAdP-NLRP6-ANXA2 complex facilitated DCV biogenesis, which enhanced antibacterial ability of intestines. Disruption of ERAdP-NLRP6-ANXA2 axis led to loss of DCVs in Paneth cells and increased susceptibility to bacterial infection. Of note, ERAdP-NLRP6-ANXA2 proteins were lowly expressed in IBD patients, and c-di-AMP treatment enhanced antibacterial capacity in antibiotic-treated mice. Our findings reveal that c-di-AMP stimulation might provide a potential therapeutic strategy for infectious disease and gut inflammation.

Inflammation-driven injury, a significant source of morbidity and mortality worldwide, is largely mediated by the cytotoxic activities of neutrophils, which extend the initial lesion and jeopardize organ function. Intriguingly, inflammatory injury naturally declines at specific times of day, suggesting that circadian mechanisms exist that mitigate the destructive activity of neutrophils and protect the host. Here, we show that the periods of diurnal protection coincide with peaks in plasma CXCL12, a chemokine that inhibits the neutrophil-intrinsic circadian clock by signaling through CXCR4. Genetic deletion of this clock, or a hyperactive form of CXCR4, prevented the diurnal spikes of injury, and treatment with a synthetic CXCR4 agonist conferred protection from myocardial and vascular injury. In tissues, this protection was mediated by repositioning neutrophils in the wound core, which spared neighboring host cells from apoptotic death. Thus, a circadian neutrophil checkpoint protects from exuberant inflammation and can be activated to protect the host.

Olfactory nerve bundles exit the brain through the cribriform plate (CP) with a rich perineural microenvironment (cpPME). This microenvironment facilitates interactions between cerebrospinal fluid, blood vessels, bone marrow, and lymphatic vessels. The immune niche of the cpPME changes in response to inflammation caused by stroke, autoimmunity, infection, and Alzheimer's disease. Neuroinflammation at the CP results in dysfunction of olfaction that might have diagnostic value in neurological disorders. Additionally, the proximity of the CP to the nasal mucosa allows targeted therapeutic interventions. A thorough understanding of the cpPME is essential for designing innovative diagnostics and treatments for neuroinflammatory diseases.

The interaction of immune cells in the lymph node microenvironment depends on the infrastructure and molecular cues provided by fibroblastic reticular cells (FRCs). In addition, concentric layers of still poorly defined mural cells, including vascular smooth muscle cells (VSMCs), are involved in positioning and regulating immune cell interactions in different lymph node compartments. Using time-resolved single-cell transcriptomics, combined with cell fate mapping and high-resolution confocal microscopy, we found that lymph node FRCs and VSMCs share a proliferating, CCL19-expressing embryonic progenitor. Trajectory analysis identified lymphotoxin β receptor (LTβR)-dependent lineages that gave rise to FRCs underpinning the subcapsular sinus, T and B cell zones, and the medulla. LTβR-independent development of VSMCs and perivascular reticular cells from the common progenitor highlighted the close developmental relationship between FRCs and mural cells. Collectively, these results indicate that CCL19-expressing perivascular progenitors are capable of generating the fibroblastic and mural cell infrastructure of murine lymph nodes.

Alzheimer's disease (AD) is characterized by the accumulation of extracellular aggregated amyloid beta, resulting from impaired waste clearance. We recently identified new cerebrospinal fluid (CSF) efflux structures termed arachnoid cuff exit (ACE) points and speculated that these may be impacted in AD, leading to impaired waste clearance function. Using 5XFAD mice, we found progressive amyloidosis of bridging veins at ACE points. Indeed, in 5XFAD mice, there is impaired CSF efflux to the dura mater, impaired CSF flow along bridging veins, and impaired blood flow through bridging veins. These observations suggest that ACE point amyloidosis plays a role in waste clearance dysfunction in AD. In postmortem human samples, we also found striking amyloidosis of the bridging veins of individuals with AD. Moreover, in human AD specimens, there was prominent bridging vein structural degeneration, indicating advanced pathology and stronger deficits in humans. We propose that bridging vein amyloidosis is an underrecognized pathophysiological correlate of AD that may impair CSF efflux, intracranial pressure, vascular reactivity, and vascular integrity.

The ability to specifically engage tumor-reactive T cells for therapeutic benefit is the ultimate goal of cancer immunotherapy. Whereas currently approved immunotherapies leverage and modulate existing endogenous T cells in an antigen non-specific manner, cancer vaccines and neoantigen therapeutics promise the ability to selectively amplify T cells specific for targeted antigens. Advances in the identification of tumor-specific antigens coupled with a greater understanding of T cell biology and immunization platforms have culminated in recent trials where signs of clinical efficacy have been observed, particularly in randomized adjuvant clinical settings. In this review, we discuss the identification of tumor-specific antigens for cancer therapy, the benefits of including antigens recognized by CD4+ T cells, clinical data investigating novel immunization platforms, and emerging clinical settings where promotion of tumor-specific immunity may be optimal.