Mycobacterium tuberculosis and TLR2 agonists inhibit induction of type I IFN and MHC-I antigen cross processing by TLR9 (37.15)

Abstract

Abstract Dendritic cells (DCs) cross process exogenous antigens and present them by MHC-I molecules to CD8+ T cells specific for antigens from viruses and bacteria such as Mycobacterium tuberculosis (Mtb). Unmethylated CpG DNA signals through TLR9 to induce type I interferon (IFN-α/β), which enhances MHC-I antigen cross processing, but lipoproteins that signal through TLR2 do not induce IFN-α/β. We observed that Mtb, which expresses agonists of both TLR9 and TLR2, did not induce IFN-α/β or cross processing by murine DCs. Furthermore, Mtb and TLR2 agonists inhibited induction of IFN-α/β and DC cross processing by CpG DNA. Exogenous IFN-α/β effectively enhanced cross-processing of Mycobacterium bovis BCG expressing OVA, bypassing the inhibition of induction of endogenous IFN-α/β. Inhibition of the response to one TLR by another may affect the ultimate response to pathogens like Mtb that express agonists of multiple TLRs, including TLR2 and TLR9. This mechanism may contribute to immune evasion and explain why IFN-α/β provides little contribution to host immunity to Mtb. On the other hand, downregulation of certain TLR responses may benefit the host by preventing detrimental excessive inflammation that may occur in the presence of persistent infection.