Researchers from the Ecole Polytechnique Fédérale de Lausanne (EPFL) report that they have pinpointed the biomolecules that initiate the growth of lymphatic vessels (lymphangiogenesis) during worm infections. The team says the exciting aspect of their work is the uncovering of a novel process underlying lymphangiogenesis that involves crosstalk between cells of the mesenteric lymph node. They believe their research will help in better understanding immune disorders and some types of cancer and may lead to new therapies for those diseases.

The study (“Interactions between Fibroblastic Reticular Cells and B Cells Promote Mesenteric Lymph Node Lymphangiogenesis”) is published in Nature Communications.

“Lymphatic growth (lymphangiogenesis) within lymph nodes functions to promote dendritic cell entry and effector lymphocyte egress in response to infection or inflammation. Here we demonstrate a crucial role for lymphotoxin-beta receptor (LTβR) signaling to fibroblastic reticular cells (FRCs) by lymphotoxin-expressing B cells in driving mesenteric lymph node lymphangiogenesis following helminth infection,” write the investigators.

“LTβR ligation on fibroblastic reticular cells leads to the production of B-cell-activating factor (BAFF), which synergized with interleukin-4 (IL-4) to promote the production of the lymphangiogenic factors, vascular endothelial growth factors (VEGF)-A and VEGF-C, by B cells. In addition, the BAFF-IL-4 synergy augments expression of lymphotoxin by antigen-activated B cells, promoting further B cell–fibroblastic reticular cell interactions. These results underlie the importance of lymphotoxin-dependent B cell–FRC cross talk in driving the expansion of lymphatic networks that function to promote and maintain immune responsiveness.”

Lymph nodes serve to clean out foreign objects and support the immune system. They communicate with tissues and each other through the lymphatic vessels, which grow during embryogenesis but also in adults during wound healing, cancer, and inflammation.

Until the EPFL announcement, how lymphangiogenesis actually took place was unclear. The lab of Nicola Harris, Ph.D., focused on the mesenteric lymph node, which collects fluids and objects from the intestines of mice. The research was led by Lalit Kumar Dubey, Ph.D., whose previous work demonstrated how worm infection stimulates B cells to “talk” to the endothelial cells of the mesenteric lymph node and start an immune response.

In the current study, the team employed immunofluorescent imaging of whole tissues to create a picture of how cells interact with each other when the mesenteric lymph node is infected with the worm Heligmosomoides polygyrus bakeri (Hpb).

The imaging showed that Hpb infection causes extensive lymphangiogenesis inside the mesenteric lymph nodes of mice, according to Dr. Dubey. An increased influx of dendritic cells also took place, indicating that an immune response had begun.

“We uncovered a multidirectional communication between B lymphocytes, fibroblasts, and lymphatic endothelial cells inside the lymph nodes,” says Dr. Harris. “This three-way communication triggers lymphangiogenesis following intestinal infection with the Hpb worm.”

The team also identified the specific biomolecules involved in this process. These include both cell-bound and secreted proteins, which the three cell types use to communicate with each other, continues Dr. Harris, who adds that the lymphangiogenesis was driven by a complex interplay between inflammatory cytokines, fibroblastic reticular cells, and B cells in the lymph node.



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