Abstract
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. 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.
Highlights
Lymphatic growth within lymph nodes functions to promote dendritic cell entry and effector lymphocyte egress in response to infection or inflammation
Using immunofluorescence staining combined with deep tissue imaging we show that Heligmosomoides polygyrus (Hp) infection results in extensive mesenteric LN (mLN) lymphangiogenesis that correlates with enhanced dendritic cell (DC) entry. mLN lymphangiogenesis was driven by a complex interplay between inflammatory cytokines, fibroblastic reticular cells (FRCs) and B cells
To determine whether intestinal helminth infection could promote mLN lymphangiogenesis we examined the entire chain of the draining mLN of naive and Hp-infected mice and visualized the lymphatic vessels by staining sections with an antibody against the lymphatic endothelial cells (LECs)-specific marker, lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE-1)
Summary
Lymphatic growth (lymphangiogenesis) within lymph nodes functions to promote dendritic cell entry and effector lymphocyte egress in response to infection or inflammation. 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. Lymphotoxin-dependent activation of mLN FRCs promoted the production of B-cell-activating factor (BAFF), which synergized with the type 2-cytokine interleukin-4 (IL-4) to activate VEGF production by B cells and to drive the proliferation of LECs. Our findings provide a novel mechanistic view of mLN lymphangiogenesis and demonstrate a previously unidentified function for FRC-derived BAFF, which provides the necessary signal for LEC expansion by programming B cells within the secondary lymphoid organs
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