Project description:DNMT3a is a de novo DNA methyltransferase expressed robustly after T cell activation that regulates plasticity of CD4+ T cell cytokine expression. Here we show that DNMT3a is critical for directing early CD8+ T cell effector and memory fate decisions. While effector function of DNMT3a knockout T cells is normal, they develop more memory precursor and fewer terminal effector cells in a T cell intrinsic manner compared to wild-type animals. Rather than increasing plasticity of differentiated effector CD8+ T cells, loss of DNMT3a biases differentiation of early effector cells into memory precursor cells. This is attributed in part to ineffective repression of Tcf1 expression in knockout T cells, as DNMT3a localizes to the Tcf7 promoter and catalyzes its de novo methylation in early effector WT CD8+ T cells. This data identifies DNMT3a as a crucial regulator of CD8+ early effector cell differentiation and effector versus memory fate decisions. Examination of global genomic DNA methylation by MBD-seq in naïve CD8 T cells and CD8 T cells 8 days post Vaccinia-Ova infection, comparing OT1 TCR-Tg CD8 T cells isolated from WT and T cell conditional DNMT3a KO mice.
Project description:B7S1 negatively regulates T cells and its expression correlates with poor prognosis of cancer patients. In order to understand how B7S1 signaling contributes to dysfunction of CD8+ T cell in the TME, we conducted transcriptional analysis of OVA-specific CD8+ TILs and different TIL subsets from E.G7-bearing WT and B7S1 KO mice (Day 21).
Project description:Expression microarrays identified 119 genes that were significantly differentially expressed in the epithelium of WT and M-NM-26 KO mice after saline or chronic allergen challenge. PAM clustering revealed two interesting clusters (6 and 8) that we had not identified in previous comparisons by whole lung microarrays. Cluster 6 genes were low at baseline in both WT and M-NM-26 KO mice and were increased in WT but not in M-NM-26 KO mice after chronic allergen challenge such as Mcpt1. Cluster 8 genes were increased at baseline in M-NM-26 KO mice, and included 6 mast cell related genes (cma1, mcpt4, cpa3, mcpt6, tpsab1, il1rl1). The most informative differentially expressed genes identified in microarrays of the epithelial microenvironment were not epithelial genes, but mast cell genes. Control and beta6 ko mice (wt-S (4), wt-OVA (4), ko-S (4), ko-OVA (4)) were sensitized and challenged with OVA or saline, airway epithelium were brush-harvested.
