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Langerhans cells regulate immunity in adulthood by regulating dermal lymphatic development in early life

ABSTRACT: The communication between skin and draining lymph nodes is crucial for immune responses to skin insults. Lymphatic vessels play critical roles in this communication by transporting antigens from skin to lymph nodes, and mechanisms that compromise dermal lymphatic function can disrupt immunity. Here, we show that Langerhans cells (LCs), epidermis-derived antigen-presenting cells, have a lymphatic-regulating role in promoting dermal lymphatic expansion and phenotype acquisition during early life. This function is mediated by PlGF and VEGF-C, and LCs have a large impact uniquely on the transcriptomic profile of lymphatic endothelial cells compared to other skin cells. Compromise of this early life LC-mediated lymphatic expansion results in reduced soluble antigen flow to draining lymph nodes and T cell responses in adulthood. Our data provide a tissue-based mechanism by which LCs regulate T cells remotely across time and space and raise the possibility that immune diseases in adulthood could reflect compromise of the LC-lymphatic axis in childhood.

ORGANISM(S): Mus musculus

PROVIDER: GSE322556 | GEO | 2026/06/19

REPOSITORIES: GEO

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Project description:Invasion of lymphatic vessels is a key step in the metastasis of primary tumour cells to draining lymph nodes. Recent evidence indicates that such metastasis can be facilitated by tumour lymphangiogenesis, although it remains unclear whether this is a consequence of increased lymphatic vessel numbers or alteration in the properties of the vessels themselves. Here we have addressed this important question by comparing the RNA profile of normal dermal lymphatic endothelial cells (LEC) with those isolated from tumours of murine T-241/VEGF-C metastatic fibrosarcoma. Our findings reveal significant changes in the expression of some 792 genes in tumour lymphatics (â?¥ 2 fold up/downregulation, p â?¤ 0.05), involving particularly transcripts associated with junctional adhesion, immunomodulation, extracellular matrix and vessel growth/patterning, several of which we have confirmed by RT-PCR and/or immunohistochemistry. Interestingly, this altered phenotype could not be attributed solely to VEGF-C induced lymphoproliferation, as no similar change in gene expression was reported when human LEC were cultured with VEGF-C in vitro. Moreover, we show that a key protein upregulated in the mouse model, namely the tight junction protein Endothelial Cell Specific Adhesion Molecule (ESAM), is similarly upregulated in tumour lymphatic vessels from 2/2 patients with head and neck squamous cell carcinoma and 4/4 patients with aggressive bladder carcinoma. These findings demonstrate a previously unrecognized influence of tumour environment on lymphatic gene expression and identify candidate tumour specific vessel markers that may prove valuable for either prognosis or therapy. Experiment Overall Design: Here we have investigated the invasion of lymphatic vessels as a key step in the metastasis of primary tumour cells to draining lymph nodes by comparing the gene expression profile of normal dermal lymphatic endothelial cells (LEC) with those isolated from tumours of murine T241/VEGF-C/GFP metastatic fibrosarcoma. Three biological replicates were analyzed from each group.

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Langerhans cells regulate immunity in adulthood by regulating dermal lymphatic development in early life

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