How intestinal immune cells discriminate between pathogenic and commensal bacteria in the gut has troubled immunologists and microbiologists alike for decades. Might the answer lie in the selective expression of Toll-like receptors (TLRs) by cells in the lamina propria, as described by Shizuo Akira and colleagues in a recent Nature Immunology paper?

TLR5 recognizes the flagella of both Gram-positive and Gram-negative bacteria and has been shown to be expressed mainly on the basolateral surface of intestinal epithelial cells. It is not, however, expressed by conventional splenic dendritic cells or macrophages, which implies an important role for TLR5 in the detection of invasive flagellated bacteria in the gut. In this study, the authors observed that CD11c+ cells in the intestinal lamina propria preferentially express TLR5 and not TLR4.

Gene-expression analysis showed that, following stimulation of CD11c+ lamina propria cells with flagellin, the expression of pro-inflammatory cytokines such as interleukin-6 (IL-6) and other immune-related proteins was induced. Interestingly, expression of the regulatory cytokine IL-10 was not induced, indicating that the response to flagellin is immunostimulatory and not tolerogenic.

By generating Tlr5-knockout mice, the authors then studied the role of TLR5 in response to commensal (Enterobacter cloacae) versus pathogenic (Salmonella enterica serovar Typhimurium) bacteria in vivo. Although wild-type CD11c+ lamina propria cells produced copious amounts of IL-6 in response to S. typhimurium, only low levels were induced by E. cloacae. Importantly, the response to the pathogenic bacteria was TLR5 dependent, as Tlr5−/− CD11c+ lamina propria cells failed to respond. This was in contrast to the response by wild-type CD11c+ splenic cells, which, although they lack TLR5 expression, responded to both S. typhimurium and E. cloacae in a TLR4-dependent manner.

So, how does the absence of this immune response in Tlr5−/− mice affect the outcome of infection with S. typhimurium? Surprisingly, Tlr5−/− mice survived infection with an otherwise lethal dose of S. typhimurium. This was probably due to the involvement of TLR5 in the transport of the bacteria from the gut to the blood and therefore in establishing lethal systemic infection, as fewer bacteria could be detected in the mesenteric lymph nodes and spleen of infected Tlr5−/− mice than infected wild-type mice.

Therefore, although selective expression of TLRs by cells in the lamina propria provides an elegant way of avoiding responses to commensal bacteria, pathogenic bacteria might have evolved ways to use this to their advantage.