GFI1-driven transcriptional and epigenetic programs maintain memory CD8+ T cell persistence [RNA-seq]

CD8+ T cells play a pivotal role in restricting chronic virus infection and provide long-term protective immunity. The molecular mechanisms that govern long-term persistence of antiviral memory CD8+ T cells are poorly understood. Growth factor independent-1 (GFI1), a transcriptional repressor, plays a crucial role in T cell development. We show that following T cell activation, GFI1 expression is selectively maintained in memory CD8+ T cells, and GFI1 marks transcriptionally distinct antiviral CD8+ T cells with superior recall and expansion capacity. Conditional deletion of GFI1 in CD8+ T cells revealed that plays a crucial role in long-term persistence of CD8+ T cells responses following chronic virus infection. Single-cell multiome sequencing demonstrated that GFI1 epigenetically controls the gene regulatory networks that promote memory CD8+ T cell proliferation. GFI1 mediated eomesodermin expression protects the CD8+ T cells from activation induced cell death. Moreover, temporal mapping revealed that continuous GFI1 expression is required to maintain long-term memory CD8+ T cells persistence. Thus, GFI1 is central regulator of the molecular programs that shape memory features and is pivotal in promoting CD8+ T cell self-renewal and long-term protective memory formation. Overall design: For transcriptional analyses of GFI1dTomato reporter CD8+ T cells, activated (CD11a+CD44+) GFI1high and GFI1low CD8+ T cells were isolated from spleen of Gfi1dTomato mice infected with LCMV clone 13 or LCMV Armstrong strains. Three samples each of GFI1high and GFI1low CD8+ T cells from both LCMV clone-13 and LCMV Armstrong infections were sequenced. To understand the transcriptional program regulated by GFI1, WT and GFI1-KO P14 T cells were adoptively transferred into congenic recipients followed by chronic LCMV clone-13 infection. Similarly, WT and GFI1-KO P14 T cells were isolated from MCMV-ie2-gp33 infected mice. Three samples each of WT and GFI1-KO CD8+ T cell isolated at day 7 following LCMV infeciton, and day 7 after MCMV infection were sequenced.