Mycobacterium tuberculosis and TLR2 agonists inhibit induction of type I IFN by TLR7/9 (116.20)

Abstract

Abstract TLR9 signaling induces type I IFN (IFN-I), which enhances MHC-I Ag cross processing, but TLR2 signaling does not. Moreover, we previously reported that TLR2 signaling by Mycobacterium tuberculosis (Mtb) or other TLR2 agonists inhibited TLR9 induction of IFN-I and IFN-I-dependent MHC-I Ag cross processing (Simmons, 2010, J. Immunol.). In the current studies, a TLR2 agonist inhibited IFN-I mRNA induction when added together with TLR9 agonist for 2 to 24 h. TLR2 agonist inhibited TLR9-induced first wave IFN-I, since the inhibition was manifested in IFN-I receptor knock out DCs, which lack the second wave positive feedback mechanism, whereas second wave IFN-I mRNA induction by exogenous IFN-I was not inhibited. TLR2 also inhibited IFN-I induced by TLR7, another MyD88-dependent IFN-inducing receptor, but did not inhibit IFN-I induction by TLR3 or TLR4 (both TRIF-dependent, MyD88-independent). The inhibitory effect of TLR2 was not dependent on new protein synthesis or intercellular signaling. Current studies are further addressing the intracellular mechanism whereby TLR2 inhibits induction of IFN-I. This novel mechanism, whereby TLR2 inhbits IFN-I induction by TLR7/9, may shape immune responses to microbes that express ligands for both TLR2 and TLR7/TLR9, or responses to bacteria/virus coinfection.