CD8+ T cells are key adaptive immune cells that are pivotal for control of virus infections and tumour surveillance and control. Upon activation, CD8+ T cells undergo a program of differentiation and proliferations whereby they acquire lineage specific functions that underpin their role in immunity. The strict control of gene expression driving CD8+ T cell differentiation is underpinned by spatial and temporal changes in chromatin biochemical modifications such as histone H3 lysine modifications. However, unlike lysine modifications, the role of histone arginine modifications in T cell differentiation is a neglected area. In this study, we demonstrate that naïve CD8+ T cell activation results in the upregulation of PRMT1 and PRMT5, the protein arginine (R) methyltransferases responsible for the asymmetric and symmetric dimethylation (me2) of histone H2A (H2AR3me2) and histone H4 (H4R3me2). This correlated with temporal increase in the level of R3me2 in activated T cells. Moreover, small molecule inhibition and CRISPR depletion of PRMTs results in disorganized expansion, IL2 signalling, tissue retention, transcription factor expression and interferon secretion within activated CD8+ T cells. These data suggest that dynamic regulation of H2AR3 and H4R3 methylation via PRMTs may play a key role in regulating chromatin structures that underpin optimal CD8+ T cell responses. These data form the basis for further studies utilising CUT&TAG to map genome wide distribution of H2A/H4R3me2 during virus-specific CD8+ T cell differentiation.