| Mycobacterium tuberculosis is responsible for more than 2 million deaths annually. Although it is well established that IFN-gamma is the critical cytokine for controlling Mtb infection, several studies have shown inhibition of IFN-gamma-induced genes in the presence of Mtb and Mtb components, such as its 19-kDa lipoprotein. In these studies, we performed microarray gene expression analysis to reveal the extent of Mtb-mediated inhibition. Interestingly, Mtb and its 19-kDa lipoprotein inhibit only a subset of IFN-gamma-induced genes (42 and 36%, respectively) while others remain unaffected or enhanced. Furthermore, we found several of the genes inhibited by Mtb are involved in antigen processing and presentation.; Class II transactivator (CIITA) expression is required for expression of MHC-II and is therefore critical for the interaction between antigen presenting cells and corresponding T cells. To elucidate the mechanism by which Mtb inhibits IFN-gamma-induced CIITA expression, we performed detailed analysis on signaling events stimulated by Mtb 19-kDa lipoprotein in the presence of IFN-gamma. We found inhibition of CIITA by Mtb and its 19-kDa lipoprotein was chromatin-dependent, as both IFN-gamma-induced histone acetylation at the CIITA promoter and recruitment of Brahma-related gene-1, part of an ATP-dependent remodeling complex, were inhibited. This mechanism was dependent on Toll-like receptor 2 and the mitogen-activated protein kinases p38 and ERK1/2 but not JNK. Mtb 19-kDa lipoprotein strongly induced expression and binding of the transcription factors CCAAT/enhancer binding protein beta (C/EBPbeta) and delta (C/EBPdelta), which may act as repressors of CIITA transcriptional activation in the presence of the lipoprotein. These studies present novel mediators of Mtb-dependent inhibition of IFN-gamma-induced genes. We hypothesize inhibition of MHC-11 presentation may provide an immunologically privileged site for the bacteria to evade immune surveillance. |
