The formation of stable and functional CD8+ T cell memory is dependent on factors present at the time of initial antigen presentation. For many infections, help from CD4+ T cells is necessary for the persistence of memory CD8+ T cells. For example, it has been previously demonstrated that establishment of effective influenza-specific CD8+ T cell memory requires CD4+ T cell help at the time of initial infection. Previous studies have described mechanisms that contribute to CD4+ T cell dependence of CD8+ T cell responses, however the precise CD8+ T cell intrinsic molecular pathways that promote and maintain memory CD8+ T cell differentiation are poorly understood. Utilising an adoptive transfer model of CD8+ TCR transgenic T cells into CD4+ T cell deficient mice, our laboratory is attempting to identify gene networks that may be differentially regulated in helped versus unhelped influenza-specific CD8+ T cells. The number of influenza-specific effector and memory CD8+ T cells were lower after transfer into CD4+ deficient mice, and as expected, unhelped memory CTL responded poorly to a secondary infection. RNA-seq analysis demonstrated that effector CD8+ T cells from CD4+ T cell deficient and sufficient mice modulated the expression of 6266 genes following stimulation, with 4697 of these shared between helped and unhelped cells. Helped CD8+ T cells expressed higher levels of several genes related to cell division and immune function, while genes upregulated in unhelped cells had signalling and immune functions. This comparison of the transcriptional profile of helped and unhelped effector CD8+ T cells reveals the genome wide cellular processes that differ between these populations, and provides information on the regulatory pathways that may control these functions.