IL-4Rα-Expressing B Cells Are Required for CXCL13 Production by Fibroblastic Reticular Cells

Summary: Adaptive type 2 immune responses against the intestinal helminth Heligmosomoides polygyrus (Hp) require the interaction of follicle-associated CXCR5+ dendritic cells with naive T cells in the draining mesenteric lymph nodes (mLNs). However, the source of CXCL13 responsible for attracting CXCR5+ dendritic cells has remained unclear. Using multiplex imaging combined with deep tissue analysis, we observed new CXCL13+ fibroblastic reticular cells surrounding paracortical and cortical B cell follicles in the mLNs of infected mice. CXCL13+ fibroblasts expressed markers of marginal reticular cells (MRCs), and their expansion required lymphotoxin (LT)-dependent interactions between IL-4Rα-expressing B cells and CCL19+ fibroblasts. Infection-induced follicles did not necessarily contain follicular dendritic cells (FDCs), indicating that CXCL13+ fibroblasts may instead drive their formation. These data reveal a role for lymphotoxin signaling to CCL19+ fibroblasts in the development of CXCL13+ MRC-like cells and adaptive type 2 immunity in response to helminth infection. : MRCs are a specialized, CXCL13-producing, stromal population located beneath the subcapsular sinus of lymph nodes. Dubey et al. demonstrate that intestinal helminth infection drives the remodeling and development of MRCs toward the paracortical region within the draining mLNs and requires the expression of type 2 cytokines and intimate B cell-stromal cell interactions. Keywords: marginal reticular cells, fibroblastic reticular cells, IL-4Rα, helminth infection, Heligmosomoides polygyrus, interfollicular region, CXCL13, mesenteric lymph node, MAdCAM-1, intestinal infectio