RT Journal Article
SR Electronic
T1 Mycobacterial Cord Factor Reprograms the Macrophage Response to IFN-γ towards Enhanced Inflammation yet Impaired Antigen Presentation and Expression of GBP1
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 1580
OP 1592
DO 10.4049/jimmunol.2000337
VO 205
IS 6
A1 Huber, Alexandra
A1 Killy, Barbara
A1 Grummel, Nadine
A1 Bodendorfer, Barbara
A1 Paul, Sushmita
A1 Wiesmann, Veit
A1 Naschberger, Elisabeth
A1 Zimmer, Jana
A1 Wirtz, Stefan
A1 Schleicher, Ulrike
A1 Vera, Julio
A1 Ekici, Arif Bülent
A1 Dalpke, Alexander
A1 Lang, Roland
YR 2020
UL http://www.jimmunol.org/content/205/6/1580.abstract
AB TDM has an ambiguous impact on the macrophage response to IFN-γ.TDM impairs IFN-γ–induced Ag presentation via MHC-II and GBP1 expression.Inhibition by TDM does not affect STAT1 phosphorylation, but requires SOCS1.Mycobacteria survive in macrophages despite triggering pattern recognition receptors and T cell–derived IFN-γ production. Mycobacterial cord factor trehalose-6,6-dimycolate (TDM) binds the C-type lectin receptor MINCLE and induces inflammatory gene expression. However, the impact of TDM on IFN-γ–induced macrophage activation is not known. In this study, we have investigated the cross-regulation of the mouse macrophage transcriptome by IFN-γ and by TDM or its synthetic analogue trehalose-6,6-dibehenate (TDB). As expected, IFN-γ induced genes involved in Ag presentation and antimicrobial defense. Transcriptional programs induced by TDM and TDB were highly similar but clearly distinct from the response to IFN-γ. The glycolipids enhanced expression of a subset of IFN-γ–induced genes associated with inflammation. In contrast, TDM/TDB exerted delayed inhibition of IFN-γ–induced genes, including pattern recognition receptors, MHC class II genes, and IFN-γ–induced GTPases, with antimicrobial function. TDM downregulated MHC class II cell surface expression and impaired T cell activation by peptide-pulsed macrophages. Inhibition of the IFN-γ–induced GTPase GBP1 occurred at the level of transcription by a partially MINCLE-dependent mechanism that may target IRF1 activity. Although activation of STAT1 was unaltered, deletion of Socs1 relieved inhibition of GBP1 expression by TDM. Nonnuclear Socs1 was sufficient for inhibition, suggesting a noncanonical, cytoplasmic mechanism. Taken together, unbiased analysis of transcriptional reprogramming revealed a significant degree of negative regulation of IFN-γ–induced Ag presentation and antimicrobial gene expression by the mycobacterial cord factor that may contribute to mycobacterial persistence.