TLR ligand sensing by lymph node FRCs directs intranodal lymphocyte accumulation to promote immune responses

Immune protection depends on antigen-responsive lymphocytes finding their cognate antigen on competent antigen-presenting cells. To increase the likelihood of such an event happening, lymphocytes transiently accumulate in secondary lymphoid organs soon after infection. Here, we show that this phenomenon requires expression of Toll-like receptors (TLRs) on lymph node stromal cells. Direct sensing of pathogen-associated molecular patterns by TLR-expressing fibroblastic reticular cells (FRCs) rapidly induced homeostatic chemokine expression, mediating immediate lymphocyte accumulation into reactive lymph nodes. Ablation of this response, by means of Tlr4 ^-/- lymph node transplantation or conditional Tlr4 gene deletion on PDGFRb⁺ cells, reduced the number of lymphocytes recruited into the immune response limiting vaccine efficacy against tumors. Taken together, these observations provide further evidence for a critical role of early FRC activation in driving effective immunity, placing these non-hematopoietic cells at the center of adaptive host protection.