<jats:title>Abstract</jats:title> <jats:p>CD5, a negative regulator of T cell receptor (TCR) signals, is a cell surface protein whose expression reflects the self-reactivity of the TCR for self-peptide. Recent studies have shown that CD5lo versus CD5hi T cells differentially respond to foreign antigen in primary and recall responses and may also have biased differentiation potential. Within the CD4+ T cell lineage, in particular, evidence points to the preferential recruitment of CD5hi CD4+ cells into the memory compartment and biased regulatory T cell development. However, the extent to which CD5 levels influence T cell differentiation and effector cytokine production is unknown. We have expanded upon these findings to show that ex vivo activated murine CD5lo CD4+ T cells produce relatively greater amounts of the Th1 cytokine IFNγ compared to their CD5hi counterparts. Interestingly, this difference is specific to IFNγ production and is not attributable to differential expression of the Th1 cell-specific transcription factor T-bet. Given the distinct metabolic programs associated with these T cell subsets and recent evidence that glycolysis regulates IFNγ production through an epigenetic mechanism, we propose that CD5 levels shape T cell function by direct or indirect regulation of cellular metabolism. Consistent with this, our preliminary data suggests that modulation of cellular acetate levels can restore IFNγ production in CD5hi cells similar to that of CD5lo cells. Our ongoing studies are focused on epigenetic and metabolic profiling of CD5lo and CD5hi cells in order to better understand the observed lineage bias.</jats:p>