Histiocytic necrotizing lymphadenopathy (HNL), a disease of unknown cause, is characterized pathologically by the presence of plasmacytoid dendritic cells (pDCs), which are frequently mixed with oligoclonal T cells (OTCs) and myeloid cells. Toll-like receptors (TLRs 1-10) are a family of pattern recognition receptors of DCs. To investigate the interactions between pDCs and T cells, and to look for an etiology of HNL, we studied 24 HNLs for the profile of TLRs. Transcripts of TLR7, a receptor on pDCs for single-stranded RNA, were found in every case, confirming the universal presence of pDCs. Transcripts of TLR9, another receptor on pDCs for microbial unmethylated CpG-rich DNA, were correlated with OTCs, implying T-cell expansion stimulated by TLR9+ pDCs in response to a microbe. Because PCRs for bacterial 16S rDNAs were negative in the lymph nodes, a bacterial origin seems unlikely, but a virus remains a possible candidate. The pDCs lacked the maturation marker CD83, which suggested ineffective stimulation of T cells and might account for the usually benign course of HNL. Taken together, these data illustrate a novel approach, based upon TLR transcript analysis, for the integration of pathology, immunology, and clinical findings of HNL.