Commensal gut bacteria have many beneficial effects for the host, including competition with pathogens and induction of the development of gut-associated lymphoid tissues. Now, Benson et al. add another function to this list by showing that the gut microbiota acts as an adjuvant to induce immunity to Toxoplasma gondii .

In mice T. gondii is sensed by Toll-like receptor 11 (TLR11) on dendritic cells (DCs), which secrete interleukin-12 (IL-12) to activate CD4+ T helper 1 (TH1) cells; these then produce interferon-γ (IFNγ) to kill the parasite. However, TLR11 is a pseudogene in humans, so a different mechanism must operate. To investigate this, the authors infected wild-type mice and Tlr11−/− mice with T. gondii. When the mice were infected orally (which mimics natural infection in humans) the production of IL-12 by DCs was reduced but not abolished in Tlr11−/− mice; by contrast, IL-12 secretion following intraperitoneal infection required TLR11. Furthermore, CD4+ T cells from Tlr11−/− mice could still produce IFNγ when the mice were infected orally but not following intraperitoneal infection. These findings indicate that the mucosal immune system can initiate immune responses to T. gondii in the absence of TLR11.

...commensal gut bacteria must indirectly stimulate immune responses against the parasite in the absence of TLR11.

Based on these findings, the authors speculated that either DCs directly detect T. gondii in a TLR11-independent manner or the gut microbiota indirectly stimulates DCs to activate TH1 cell responses. DCs isolated from the intestine of Tlr11−/− mice could not detect the parasite in vitro, indicating that TLR11 is required for this process. However, depletion of the gut microbiota in Tlr11−/− mice abolished the production of IL-12p40 (a component of IL-12) by DCs and subsequent immune responses to the parasite. Therefore, commensal gut bacteria must indirectly stimulate immune responses against the parasite in the absence of TLR11. This TLR11-independent activation of immune responses was found to result in reduced immunopathology compared with TLR11-dependent stimulation, with wild-type mice showing marked immune-mediated damage in the small intestine and significantly higher mortality than Tlr11−/− mice.

So how do commensal gut bacteria trigger adaptive immune responses against T. gondii? Oral infection of mice lacking TLR9 or both TLR2 and TLR4 (which are used by DCs to sense bacteria) resulted in a marked decrease in IFNγ production by CD4+ T cells. These TLRs signal through myeloid differentiation primary response protein 88 (MYD88), lack of which (in Myd88−/− mice) abolished IL-12p40 production following oral or intraperitoneal infection with T. gondii. Together, these observations suggest that commensal bacteria stimulate TLR2 and TLR4, or TLR9, of DCs, which signal through MYD88 to mediate DC activation and the induction of TH1 cell-mediated immunity against T. gondii. Further studies will be required to determine how DCs differentiate between commensal and pathogenic bacteria, and how commensal bacteria induce parasite-specific T cell responses without triggering an antibacterial immune response.