Chemical and genetic control of IFN γ‐induced MHCII expression

Abstract

The cytokine interferon-γ (IFNγ) can induce expression of MHC class II (MHCII) on many different cell types, leading to antigen presentation to CD4 T cells and immune activation. This has also been linked to anti-tumour immunity and graft-versus-host disease. The extent of MHCII upregulation by IFNγ is cell type-dependent and under extensive control of epigenetic regulators and signalling pathways. Here, we identify novel genetic and chemical factors that control this form of MHCII expression. Loss of the oxidative stress sensor Keap1, autophagy adaptor p62/SQSTM1, ubiquitin E3-ligase Cullin-3 and chromatin remodeller BPTF impair IFNγ-mediated MHCII expression. A similar phenotype is observed for arsenite, an oxidative stressor. Effects of the latter can be reversed by the inhibition of HDAC1/2, linking oxidative stress conditions to epigenetic control of MHCII expression. Furthermore, dimethyl fumarate, an antioxidant used for the treatment of several autoimmune diseases, impairs the IFNγ response by manipulating transcriptional control of MHCII We describe novel pathways and drugs related to oxidative conditions in cells impacting on IFNγ-mediated MHCII expression, which provide a molecular basis for the understanding of MHCII-associated diseases.

Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells

“…Our analysis found the previously-described negative regulators, Irf2 (87), Keap1, and Cul3 (88)(89)(90) in the PD-L1-related Cluster 7, along with novel putative negative regulators such as the oligosaccharlytransferase complex subunit Ostc and the transcriptional regulator, Cnbp. We generated knockout macrophages for each of these novel candidates and confirmed that mutation of these genes enhances the IFNg-dependent induction of PD-L1 surface levels ( Figure 1F).…”

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…Drugs and environmental contaminants have been shown to contribute to immune deficiency. Substances inducing oxidative stress such as sodium arsenite (≥1 µM NaAs 2 O 3 ), or the antioxidant dimethyl fumarate (≥25 µM DMF; autoimmune disease drug) and tertbutylhydroquinone (≥25 µM tBHQ) reduce INFγ-induced (100 ng/mL) MHC-II (HLA-DR) surface protein expression in HeLa and in U118 cell lines and consequently reduce the efficiency of the immune system [529]. The effects of arsenite are mediated by the inhibition of the oxidative stress sensor KEAP1 (which also mediates NRF2-dependent antioxidant gene expression), and inhibition of H4K16 histone acetyltransferase MYST1, both involved in INFγ pathway inducing MHC-II surface protein expression.…”

“…The effects of arsenite are mediated by the inhibition of the oxidative stress sensor KEAP1 (which also mediates NRF2-dependent antioxidant gene expression), and inhibition of H4K16 histone acetyltransferase MYST1, both involved in INFγ pathway inducing MHC-II surface protein expression. The antioxidant DMF is a broad regulator of INFγ-induced MHC-II and chemokine expression acting through multiple pathways [529].…”

A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation

“…The IFN-dependent control of MHCII is complex (5,12,(17)(18)(19). Binding of IFN to its receptor induces cytoskeletal and membrane rearrangement that results in the activation of Janus kinases 1 and 2 (JAK1 and JAK2) and STAT1-dependent transcription (20,21).…”

“…MHCII is also regulated posttranslationally to control the trafficking, peptide loading, and stability of MHCII on the surface of cells (25)(26)(27). While recent evidence points to additional regulatory mechanisms of IFNmediated MHCII expression, including the response to oxidative stress, these have not been investigated directly in macrophages (17).…”