Journal of Experimental Medicine最新文献

Afferent lymphatic vessels (LVs) are present in most vascularized tissues and exert important immune and drainage functions, yet human afferent LVs remain poorly studied. Performing single-cell RNA sequencing of lymphatic endothelial cells (LECs) from human skin and subcutaneous adipose tissue, we identified various LEC subsets, including two valve LEC populations located on the upstream and downstream sides of the valve leaflets. The cell adhesion molecule CD24 emerged as a specific marker of upper valve leaflet LECs in human skin and contributed to lymphatic valve development in murine mesentery. Three-dimensional imaging further revealed several unique features of the human dermal lymphatic network, including a high proportion of LYVE-1+ pre-collecting vessels containing intraluminal valves, virtually no collectors, and absence of lymphatic muscle cell coverage. Moreover, LECs in blind-ended capillaries and around valves in pre-collectors displayed mixed junctional and morphological phenotypes. These findings reveal key differences between human and murine dermal afferent lymphatics and provide a deeper understanding of human lymphatic-related (patho)physiological processes.

Spleen conventional dendritic cells type 1 (cDC1) take up apoptotic cells (AC) and cross-present associated antigens to CD8 T cells. The receptors promoting AC uptake are incompletely defined. Here, we tested the function of GPR34, a receptor that responds to the phosphatidylserine (PS) catabolite lysoPS. GPR34 deficiency led to reduced AC uptake by cDC1 but not cDC2 or macrophages. Uptake of soluble antigen or heat-killed bacteria was unaffected, whereas uptake of eryptotic RBCs was reduced. Using AC harboring OVA, activation and proliferation of OT-I T cells were compromised in GPR34-deficient mice. Reciprocally, GPR34 overexpression led to enhanced AC uptake and OT-I proliferation. The enzymes PLA1A and ABHD16A have been implicated in generating lysoPS that can act on GPR34. PLA1A but not ABHD16A deficiency was associated with a reduced OT-I response to AC-associated OVA. In conclusion, we identify a receptor requirement for cDC1 efferocytosis and cross-presentation and suggest a model where PLA1A catabolizes PS on AC to generate GPR34 ligands.

Gains of chromosome 12p11.21, encoding for the cancer-specific lncRNA LISRR, correlate with poor survival across different cancers. In melanoma, LISRR is upregulated in immunotherapy-resistant patients to contribute to the generation of drug-tolerant cells by activating an immune-suppressive translational program, affecting the synthesis of PD-L1 and of the glycocalyx. Accordingly, downregulation of LISRR initiates robust immune responses and resensitizes to immunotherapy ex vivo and in vivo. The use of glycans to evade immunity exhibits shared characteristics with the testis, where defects in the glycocalyx cause infertility. Mechanistically, we showed that LISRR affects the ribosome core composition and recruits deleted in azoospermia-associated protein 1 to polysomes to prime the integrated stress response. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based strategy to overcome resistance to immune checkpoint blockade.

Tumor necrosis factor α (TNFα) maintains homeostasis through promoting cell survival or cell death; however, how this process is regulated by metabolic pathways remains largely unknown. Here, we identify adenosine kinase (ADK), the key enzyme for catalyzing the conversion of adenosine to AMP, as an endogenous suppressor of RIPK1 kinase. ADK-mediated adenosine metabolic clearance is a prerequisite for transmethylation reactions on various cellular targets. We found that ADK licenses constitutive R606 symmetric dimethylation in RIPK1 death domain (DD), which is catalyzed by protein arginine methyltransferase 5. Upon TNFα stimulation, DD-mediated RIPK1 dimerization is inhibited by R606 methylation, preventing RIPK1 kinase activation and keeping cell death in check. Both hepatocyte-specific ADK knockout and systemic ADK inhibition cause spontaneous RIPK1-driven hepatocyte death, which leads to hepatic homeostasis disruption. Furthermore, ADK is reduced in hepatic ischemia-reperfusion, aggravating hepatic injury during liver surgery. Thus, this study reveals a mechanism of adenosine metabolism-dependent homeostasis maintenance that is implicated in both physiological and pathological conditions.

Antigen-specific oral tolerance prevents harmful immune responses in naïve animals but is difficult to induce in antigen-primed hosts. Here, we showed that feeding of antigen-containing diet generated peripherally derived regulatory T (pTreg) cells with tissue-adapted effector properties. They acquired Treg-specific epigenomic changes at Treg signature genes, including Foxp3, exhibiting stable suppressive function. Cessation of antigen feeding diminished pTreg cells, hampering tolerance induction. Notably, pTreg cells induced by antigen feeding predominantly expressed CD101. CD101+ Treg cells with similar phenotypic and epigenetic features could also be generated in vitro from antigen-primed naïve CD4+ T cells by blocking CD28-mediated costimulation during TGF-β-dependent Treg induction. Furthermore, in mice already antigen-sensitized by nonoral routes, in vivo blockade of CD28 signaling with CTLA4-Ig prior to antigen feeding promoted differentiation of antigen-specific T cells into CD101+ pTreg cells, facilitating oral tolerance. Thus, continuous oral antigen exposure combined with CD28 blockade generates functionally stable CD101+ pTreg cells, thereby establishing systemic antigen-specific tolerance even in antigen-presensitized hosts.

Ulcerative colitis (UC) is primarily characterized by inflammation-induced tissue damage, but impaired tissue repair also drives disease progression. This study demonstrates group 2 innate lymphoid cells (ILC2s), key players in tissue repair, are dysfunctional in UC and experimental colitis due to disrupted endoplasmic reticulum protein processing. We show that the pro-repair function of gut ILC2s depends on the IRE1α-Xbp1 branch of unfolded protein response (UPR), supported by IL-25 and suppressed by interferon-γ (IFN-γ). During colitis, loss of IL-25 and rise of IFN-γ hinder Xbp1 mRNA splicing, weakening ILC2s' ability to mediate tissue repair. Mechanistically, spliced Xbp1 drives folate-dependent one-carbon (1C) metabolism by promoting dihydrofolate reductase expression. Translationally, the 1C metabolite adenosine 5'-monophosphate alleviated colitis in both ILC2-specific Xbp1 knockout and wild-type mice. Our findings highlight the UPR's role in sensing gut environment to regulate ILC2 function and suggest folate-mediated 1C metabolism as a potential target for UC therapy.

Interferon regulatory factors (IRFs) are a family of transcription factors essential for immune system development and host defense. Beyond immunity, IRF6 plays an indispensable role in craniofacial development. Inborn errors of IRFs (IE-IRFs) are a group of rare monogenic disorders caused by damaging variants in the IRF family of genes. In this review, we comprehensively discuss known IE-IRFs and how they contribute to our understanding of human biology, and provide a framework for their diagnosis and treatment. The IRF transcription factors mediate a wide range of biological functions. Accordingly, genetic defects in individual IRFs give rise to diverse human phenotypes, including increased susceptibility to infection, impaired immune development, and even congenital anatomical anomalies. Our collective understanding of IE-IRFs is a powerful example of how integration of clinical care with mechanistic translational research can transform the lives of patients while simultaneously advancing our fundamental understanding of human biology.

Metastatic progression is a major cause of radiotherapy (RT) failure, yet the mechanisms linking RT to immune suppression and metastasis remain unclear. Here, we identify YTHDF2 as a radiation-induced immune checkpoint in dendritic cells (DCs). By analyzing patient biopsies from a clinical trial (NCT03223155), we discover that increased YTHDF2 expression in DCs after RT correlates with treatment failure after RT. Mechanistically, ionizing radiation induces SPI1, which drives transcription of Ythdf2 in DCs. Upregulated YTHDF2 promotes m6A-mediated degradation of Notch pathway regulators (Mfng, Aph1b, Aph1c), impairing MHC-I cross-presentation and CD8+ T cell activation, thereby facilitating tumor immune evasion and metastatic spread. Crucially, targeting YTHDF2 restores DC immunogenicity, enhances RT-induced tumor control, and improves DC-based cancer vaccines when combined with RT, providing a clinically actionable strategy to overcome RT resistance and metastasis.

Apoptotic cell (AC) corpses can be taken up by certain types of dendritic cell (DC), which cross-present dead cell-derived antigens. In this issue of JEM, Tam et al. (https://doi.org/10.1084/jem.20250887) reveal that GPR34, a lysophosphatidylserine receptor, promotes AC uptake and cross-presentation by type 1 DCs (cDC1s).

Currently, it remains largely unclear how MSI-H/dMMR tumors, despite heightened immune pathway activation and antigenic mutation accumulation, evade immune elimination and promote tumorigenesis. Our study showed that dMMR tumors accumulate cytosolic double-stranded DNA, activating the cGAS-IFN pathway and upregulating DNA-digesting enzyme TREX1. In immunocompetent mice, Trex1 depletion in MSI-H/dMMR tumors abolished tumor formation in a CD8+ T cell-dependent manner, suggesting its critical role in enabling these tumors to evade immune attack. Mechanistically, Trex1 loss amplified tumor-intrinsic cGAS-STING signaling, promoted the activation of CD8+ T cells, and triggered systemic antitumor immunity. Critically, ablating cGAS-STING signaling in MSI-H/dMMR tumors abolished the immune boost from TREX1 deletion, revealing the critical role MSI-H/dMMR tumor-intrinsic cGAS-STING pathway. Furthermore, Trex1 inhibition specifically reduced MSI-H/dMMR tumors growth in vivo, highlighting its clinical potential. Together, we identify the cGAS-STING-TREX1 loop as a key immune escape mechanism in MSI-H/dMMR cancers, suggesting TREX1 inhibition could enhance immunotherapy for these patients.