Infectiology Forum: Dr. Sebastian AMIGORENA
Date / Heure
Date(s) - 23/05/2019
10 h 00 min - 11 h 00 min
Amphi Pasteur, Tour CERVI
Dr. Sebastian AMIGORENA (Head of the Immunology Department INSERM U932 – Cancer Immunity Curie Institute – Paris), ” Epigenetic control of CD8+ T cell immune responses to tumors ”
Following activation by antigens, naïve CD8+ T lymphocytes establish specific heritable gene expression programs that define progression to long-lasting memory cells, to short-lived effector cells, or to “exhausted” dysfunctional cells, in chronic infections or tumors. How chromatin dynamics contributes to controlling gene expression programs in differentiating CD8+ T cells is still poorly understood. We have explored the role of heterochromatin-mediated gene expression silencing by Suv39h1, a histone H3 lysine 9 methyltransferases that plays a critical, evolutionary conserved, role in heterochromatin dynamics. After Listeria monocytogenes infection, Suv39h1-dependent H3K9me3 deposition controls the expression of a set of stem cell related/memory genes. As a result of defective memory gene silencing, Suv39h1-defective CD8+ effector T cells show increased memory potential, including sustained survival and stronger long-term re-programming capacity, as compared to Suv39h1-proficient CD8+ T cells. The effect of Suv39h1-inhibiton in the context of anti-tumor immune responses, CD8+ T cell dysfunction and re-programing by checkpoint blockade was analyzed using single cell RNAseq of tumor infiltrating T cells. We show that Suv39h1 expression is required for progression of T cells to exhaustion, and that in the absence of Suv39h1 expression, CD8T T cells are more sensitive to re-programing by anti-PD-1 treatment. Our results show that gene expression silencing by heterochromatin controls stem/memory functions during effector and exhausted CD8+ T cell differentiation, both in infectious and tumor-specific immune responses.