Toll-like receptor 2 suppresses Toll-like receptor 9 responses in Peyer's patch dendritic cells

In the intestine, immune responses to commensal microbes should be regulated precisely. This regulation is achieved partly by dendritic cells (DCs), which recognize microbes through Toll-like receptors (TLRs). Although TLR responses have been intensely studied, cross-talk between individual TLRs remains unclear. The present study shows that TLR2 suppressed TLR9-induced Il12b gene expression and subsequent interleukin (IL)-12 and IL-23 production in DCs from Peyer's patch, a lymphoid tissue in the small intestine. The DCs expressed Il12b gene and produced IL-12 and IL-23 in response to TLR9 stimulation, and these responses were suppressed when the DCs were stimulated simultaneously with TLR2. The suppression was also observed in the non-intestinal DCs, such as spleen DCs and bone marrow-derived DCs. Peyer's patch DCs expressed Il12b gene also in response to TLR7 or CD40 stimulation, but these responses were not suppressed by simultaneous TLR2 stimulation. In addition, TLR9-induced Tnf and Il6 gene expression was not suppressed by TLR2. Furthermore, the supernatant of TLR2-stimulated DCs could not suppress TLR9-induced Il12b gene expression. These results suggest that TLR2 suppress TLR9-induced responses selectively, and this suppression is not mediated by secretory factors. The suppressive TLR cross-talk might play a certain role in preventing excess inflammatory responses to commensal microbes in the intestine and may have implications for the therapeutic strategies for intestinal inflammatory diseases, autoimmune diseases and cancer.