Alerting dendritic cells to pathogens: The importance of Toll-like receptor signaling of stromal cells

Eradication of intracellular pathogens relies on differentiation of naïve CD4⁺ T cells into T helper (Th) 1 cells that produce IFN-γ, which promotes macrophage activation and production of complement-fixing and opsonizing antibodies (1-3). CD4⁺ T cells differentiate into Th1 cells by following instructions provided by dendritic cells (DCs) that have perceived pathogen incursion through specific receptors for microbial components, the Toll-like receptors (TLRs) (4). In this issue of PNAS, Sato and Iwasaki (5) demonstrate that TLR-mediated vigilance of DCs alone is not sufficient to trigger Th1 responses against intracellular pathogens. In fact, they show that epithelial and stromal cells, which constitute the mucosal barrier primarily attacked and infected by pathogens, also generate TLR-mediated signals that contribute to initiation of Th1 responses (5).

DCs are bone marrow-derived cells that seed peripheral tissues and function as sentinels of pathogenic invasion (6). Upon detecting the presence of infectious agents, DCs capture microbial antigens and deliver them to draining lymph nodes (6). There, DCs present microbial antigens to rare antigen-specific naïve CD4⁺ T cells, triggering their proliferation and expression of the functional receptor for IL-12 (IL-12R) (1, 3, 6) (Fig. 1). Moreover, …