Journal of Experimental Medicine最新文献

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.

In this issue of JEM, Zhang et al. (https://doi.org/10.1084/jem.20250025) describe complete T cell antigens (CTAs), comprised of class I and class II immunogenic peptides fused in a single polypeptide that greatly increase the effectiveness of cancer immunotherapy, even when the CTA antigens are not expressed in tumor cells.

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 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.

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.

Perivenous tunnels surrounding bridging veins terminate at "arachnoid cuff exit" (ACE) points, which enable waste efflux from the brain. Smyth et al. (https://doi.org/10.1084/jem.20251860) show that amyloid deposits in ACE in Alzheimer's disease mice and human samples identify a potential new therapeutic target.

Foxp3+ regulatory T (Treg) cells co-expressing RORγt adopt specialized functions to restrain intestinal inflammation. However, despite extensive characterization, the factors governing RORγt+Foxp3+ Treg specialization remain unclear. Here, we report that transcriptional repressor REV-ERB is critical for the differentiation and function of colonic RORγt+Foxp3+ Treg cells. REV-ERB deficiency exacerbates both TNBS- and oxazolone-induced intestinal inflammation. Mechanistically, REV-ERB promotes RORγt expression through suppressing the expression of transcriptional repressor Bhlhe40, which in turn inhibits c-Maf, a key factor promoting colonic RORγt+Foxp3+ Treg differentiation and function. Moreover, this Bhlhe40-c-Maf axis downstream of REV-ERB also regulates the expression of core colonic Treg signature genes including IL-10 and CTLA-4, while REV-ERB additionally safeguards RORγt+Foxp3+ Treg functional stability by directly suppressing proinflammatory cytokine IL-17A production. Collectively, the present study identifies that REV-ERB along with the downstream Bhlhe40-c-Maf axis jointly controls the RORγt+Foxp3+ Treg differentiation and suppressive function, suggesting that modulating their activities may strengthen RORγt+Foxp3+ Treg function to ameliorate inflammatory bowel diseases.

Hematopoietic stem/progenitor cells (HSPC) aging has long been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across the human lifespan has been lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis from youth to advanced age. Although primitive hematopoietic stem cell (HSC) numbers were stable during aging, overall cellularity declined, especially for erythroid and lymphoid lineages. HSPCs from older individuals exhibited repopulating frequencies comparable with those from younger donors in both primary and secondary xenografts; however, aged HSCs displayed impaired differentiation, chromatin and cell cycle dysregulation, and poor tolerance to activation-induced proliferative stress, resulting in DNA damage and senescence-like features after xenotransplantation. Importantly, imposing proliferative stress on young human HSPCs in vivo recapitulated key aging-associated phenotypic and functional declines. Together, our findings identify dysregulated activation responses as a defining feature of HSPC aging and establish proliferative stress-based xenotransplantation models as powerful platforms for investigating age-related hematopoietic dysfunctions.

Clonal hematopoiesis driven by Tet2 deficiency in myeloid cells (TetΔMye) is prevalent in elderly individuals; however, the role of Tet2ΔMye in liver fibrosis pathogenesis remains elusive. In this study, we demonstrated that Tet2-deficient monocyte-derived macrophages (MDMs) promoted cellular expansion and elevated C-C motif chemokine ligand 2/8 (Ccl2/8) secretion by stabilizing their mRNAs through 5hmC-mediated alterations in RNA-protein interactions. These chemokines engaged with the upregulated C-C motif chemokine receptor (Ccr2/3) on Tet2-/- monocytes, forming a positive feedback loop that amplified pro-inflammatory MDMs (pMDMs) accumulation in liver. Tet2-/- pMDMs activated hepatic stellate cells through IL-6, driving extracellular matrix deposition and fibrotic progression. Pharmacological inhibition of Ccl2/Ccl8 with Bindarit attenuated MDMs accumulation and liver fibrosis, whereas combined therapy with Bindarit and IL-6 neutralization synergistically suppressed liver fibrosis in Tet2ΔMye mice and aged chimeric models recapitulating Tet2ΔMye-related myeloid hematopoiesis. These findings present the mechanism that Tet2ΔMye aggravates liver fibrosis and highlight MDMs depletion plus IL-6 neutralization as a promising therapy for liver fibrosis in patients with Tet2ΔMye-related myeloid hematopoiesis.