Rescuing “helpless” CD8+ T cell Memory Responses by Activating NK Receptor NKG2D during Priming

Abstract

It has been shown that memory CD8+ T cells that have been generated in the absence of CD4 help are defective in their ability to respond to secondary antigen encounter. This decline in antigen reactivity was not due to a loss of memory T cells but rather the development of a “helpless” memory CD8 T cell. Natural killer receptor, NKG2D is a cell surface receptor expressed on NK cells and some T cells. On CD8+ T cells, it can amplify signals through the TCR and thus, function as a co-stimulatory molecule. These studies were developed to investigate the potential of augmenting CD8+ T cell effector and memory responses by engaging NKG2D during vaccination in the presence and absence of CD4+ T cell help. In order to better understand the role of NKG2D in CD8+ cell priming, we have activated this receptor by co-delivering DNA encoding its ligands, retinoic acid-inducible RAE-1e or H-60 during DNA vaccination against ovalbumin (OVA) in vivo. We found that addition of these ligands leads to enhanced antigen recognition as displayed by intra-cellular IFN-g release as well as increased cytotoxicity against OVA targets. Importantly, if these ligands are delivered in the absence of CD4 help, the ‘helpless” memory phenotype of CD8+ T cells is reversed and secondary antigen reactivity is rescued.