Mycobacterium tuberculosis is responsible for more than 2 million deaths annually. Although it is well established that IFN-γ is the critical cytokine for controlling Mtb infection, several studies have shown inhibition of IFN-γ-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-γ-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-γ-induced CIITA expression, we performed detailed analysis on signaling events stimulated by Mtb 19-kDa lipoprotein in the presence of IFN-γ. We found inhibition of CIITA by Mtb and its 19-kDa lipoprotein was chromatin-dependent, as both IFN-γ-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/EBPβ) and delta (C/EBPδ), 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-γ-induced genes. We hypothesize inhibition of MHC-II presentation may provide an immulogically privileged site for the bacteria to evade immune surveillance.