Mycobacterium tuberculosis-derived mycolic acid shows an adjuvant activity by activation of the ITAM receptor/CARD9-mediated innate immunity (#207)
Mycobacterium tuberculosis contains various components that affect host immune systems and its derivatives have been used as an adjuvant. Among the components, trehalose-6,6’-dimycolate (TDM) has been reported to activate Syk-Card9 signaling pathway through a C-type lectin receptor, Mincle, in antigen-presenting cells for induction of pro-inflammatory cytokine production. Given that Mincle-deficient mice, as well as other mice deficient for a receptor that recognizes other M. tuberculosis-derived components, showed substantial resistance to M. tuberculosis infection, we explored other mycobacterial cell wall components that activate innate immunity through the ITAM receptor/CARD9 pathway. Among candidate ligands and corresponding receptor combinations we have identified, mycolic acid (MA) activated Syk-Card9 signaling pathway through an ITAM-coupled receptor other than Mincle. To evaluate the potential of MA as an adjuvant, we analyzed the immunostimulatory activities of MA. For this purpose, we immunized mice once with ovalbumin (OVA) alone, OVA plus MA, or OVA in incomplete Freund's adjuvant, and OVA-specific immune responses were evaluated. OVA plus MA-immunized mice showed higher titers of OVA-specific antibodies than other groups. T cells from OVA plus MA-immunized mice showed augmented production of IFN-γ, as a parameter of Th1 response, over OVA plus IFA-immunized mice. These data demonstrate that MA has a potent adjuvant activity to enhance Th1 responses. Identification of the corresponding receptor, examination of how MA stimulates the innate immunity, and evaluation of the adjuvant activity of MA in other settings such as infection are currently in progress.