Speaker: Sebastian Amigorena, PhD - Institut Curie - Paris - France
Organizers: IRB Barcelona
Date: Friday 21 February 2020, 12.00h
Place: Felix Serratosa Hall, Parc Cientific de Barcelona
Host: Manuel Serrano, PhD - IRB Barcelona
After priming, naïve CD8+ T lymphocytes implement heritable gene expression programs that define differentiation to memory or short-lived effector cells. Even if lineage specification in T cells is indispensable for protection, the modalities of chromatin dynamics that contribute to the control gene expression programs remain unclear.
We explored the role of heterochromatin-mediated gene expression silencing by Suv39h1, a histone H3 lysine 9 methyltransferases critical for heterochromatin dynamics, in memory – effector differentiation. In CD8+ T cells activated after Listeria monocytogenes infection, Suv39h1-dependent H3K9me3 deposition determines the silencing of a set of stem cell-related/memory genes. In conditions of chronic stimulation, including during anti-tumor immune responses, cells enter a distinctive differentiation program that ultimately leads to loss of effector functions (sometimes referred to as “exhaustion” or dysfunction”). We found that Suv39h1 promotes to this differentiation program through silencing of memory features in chronically stimulated intratumor T cells.
In dendritic cells (DCs), Suv39h1 and heterochromatin also limit anti-tumor immune responses, but through a totally different mechanism, involving silencing the expression of endogenous retroelements. During innate activation, DCs rapidly extinguish the expression of the histone 3 lysine 9 (H3K9) methyltransferase Suv39h1, reducing H3K9 trimethylation (H3K9me3) levels at transposable element (TE) loci. As a consequence, TE expression is de-repressed and TE DNA, exposed to cGAS. Maximal IFN-I production during innate activation by LPS requires DNA-binding competent cGAS. Cytosolic cGAS immunoprecipitation and high throughput sequencing identify specific LINE1 subfamilies as principle endogenous ligands for cGAS. Consistently, ablation of Suv39h1 amplifies TE expression and exacerbates production of IFN-I and anti-tumor immunity, while cGAS-deficit has opposite effects. Thus, stimulation of primary DCs with an exogenous pathogen associated molecular pattern (PAMP), epigenetically activates endogenous PAMPs (unshielded endogenous viral ligands) that engage innate sensing pathways.