The molecular basis of CD4+ T cell priming for CD8+ T cell memory formation

Abstract

Abstract A long-lived pool of potent memory cells is the defining feature of adaptive immunity. Memory CD8 T cells offer protection for the life of the host due to their unique capabilities to survive in the absence of antigen and respond rapidly to secondary challenge. Therefore, effective CD8 T cell memory is the goal of cell-mediated vaccination strategies. While it is well established that CD4 help is required for CD8 T cell memory formation, it is unclear when during CD8 differentiation this help is required. Further, the affect that CD4 help has on the transcriptional profiles of CD8 T cells and the molecular pathways they use during the generation and maintenance of memory CD8 T cells remains elusive. Using a mouse model of Influenza A virus infection, where priming occurs in the presence or absence of CD4 T cell help, we have pinpointed that help is required during the initial priming of CD8 T cells, and not during memory maintenance or recall. Genome wide RNA-sequencing analysis of the transcriptional signatures between resting “helped” and “ unhelped” memory CD8 T cells reveals surprisingly few differentially expressed genes. However, upon reactivation, “helped” memory CD8 T cells exhibited greater transcriptional up regulation than their “unhelped” counterparts, and utilization of alternate molecular pathways. Our analysis revealed that CD4 help during initial priming is essential for establishing a memory cell pool with enhanced transcriptional potential. Intriguing metabolism differences are currently being further dissected based on this RNA-sequencing data. Thus, CD4 T cell dependent programming likely underpins rapid responsiveness, a key characteristic of memory CD8 T cells.