Toll -like receptor -dependent inhibition of macrophage interferon -gamma induced responses by Mycobacterium tuberculosis and its 19-kilodalton lipoprotein

Mycobacterium tuberculosis (MTB) persists inside the host for an extended period of time despite vigorous immune responses. The mechanism by which MTB maintains latent infection remains unclear. Here we show that MTB and its 19-kilodalton (kDa) lipoprotein inhibit the ability of interferon-gamma (IFN-gamma) but not interleukin-4 to activate macrophages to present antigen onto class II major histocompatibility complex (MHC-II) as measured by activation specific CD4-restricted T hybridoma cells. Inhibition of MHC-II antigen processing was shown to involve decreased transcription of MHC-II.;Induction of MHC-II expression is critically dependent on the class II transactivator (CIITA). We show that IFN-gamma induces expression of both type I and type IV class II transactivator but expression of the different types is maintained with different kinetics. In addition, induction of both types of CIITA by IFN-gamma was prevented by infection with MTB or treatment with MTB 19-kDa lipoprotein. Inhibition of MHC-II Ag processing and MHC-II expression by MTB 19-kDa lipoprotein was not observed in macrophages deficient in Toll-like Receptor (TLR) 2 or the adapter molecule MyD88. Inhibition of Ag processing by MTB was partially dependent on TLR 2 but critically dependent on MyD88.;We hypothesized that MTB and its 19-kDa lipoprotein prevents the ability of IFN-gamma to induce a large number of genes. Consistent with our hypothesis, microarray analysis revealed that induction of a large number of the genes by IFN-gamma was inhibited by infection with MTB (53%) or treatment with MTB 19-kDa lipoprotein (60%). These results were not seen in MyD88-/- macrophages. Many of the inhibited genes were involved in T-cell recruitment and activation; however, host defense genes were spared from inhibition. We believe inhibition of IFN-gamma induced responses by 19-kDa lipoprotein could contribute to persistence of MTB infection by decreasing the ability of an infected macrophage to activate CD4+ T-cells.