ARS2-directed alternative splicing mediates CD28 driven T cell glycolysis and effector function

CD8 T cell activation prompts extensive transcriptome remodeling underlying effector differentiation and function. Regulation of transcriptome composition by the mitogen-inducible nuclear cap-binding complex (CBC) adaptor protein ARS2 has critical cell type-specific consequences, including thymic T cell survival. Here we show that ARS2 was upregulated by CD28 during activation of peripheral T cells, was essential for anti-tumor immunity, and facilitated T cell activation-induced alternative splicing. The novel splicing function of ARS2 was mediated at least in part by recruitment of splicing factors to nascent transcripts including the M2 isoform of pyruvate kinase ( Pkm2 ), a key determinant of CD8 T cell effector properties. Notably, ARS2-directed Pkm2 splicing occurred days after stimulation of PI3K-indepdendent CD28 signaling and increased glycolysis beyond levels determined by PI3K signaling during T cell priming. Thus, ARS2-directed Pkm2 splicing represents a mechanism by which CD28 drives glycolytic metabolism, allowing for optimal effector cytokine production and T cell anti-tumor immunity.