Natural killer group 2D and CD 28 receptors differentially activate mammalian/mechanistic target of rapamycin to alter murine effector CD 8 + T‐cell differentiation

Memory CD 8 + T cells are an essential component of anti‐tumour and anti‐viral immunity. Activation of the mammalian/mechanistic target of rapamycin (m TOR ) pathway has been implicated in regulating the differentiation of effector and memory T cells. However, the mechanisms that control m TOR activity during immunity to tumours and infections are not well known. Activation of co‐stimulatory receptors, including CD 28 and natural killer group 2D ( NKG 2D), activate phosphatidylinositol‐3 kinase and subsequently may activate the m TOR pathway in CD 8 + T cells. This study compared the activation of the m TOR signalling pathway after co‐stimulation through CD 28 or NKG 2D receptors in murine effector CD 8 + T cells. Compared with CD 28 co‐stimulation, activation through CD 3 and NKG 2D receptors had weaker activation of m TOR c1, as shown by decreased phosphorylation of m TOR c1 targets S6K1, ribosomal protein S6 and eukaryotic initiation factor 4E binding protein 1. NKG 2D co‐stimulation also showed increased gene expression of tuberous sclerosis protein 2, a negative regulator of m TOR c1, whereas CD 28 co‐stimulation increased gene expression of Ras homologue enriched in brain, an activator of m TOR c1, and hypoxia‐inducible factor‐1 α and vascular endothelial growth factor‐ α , pro‐angiogenic factors downstream of m TOR c1. Strong m TOR c1 activation in CD 28‐co‐stimulated cells also increased expression of transcription factors that support effector cell differentiation, namely T‐bet, B lymphocyte‐induced maturation protein (BLIMP‐1), interferon regulatory factor 4, and inhibitor of DNA binding 2, whereas low levels of mTOR c1 activation allowed for the expression of Eomes, B‐cell lymphoma 6 (BCL6), and inhibitor of DNA binding 3 during NKG 2D stimulation, and increased expression of memory markers CD 62 ligand and CD 127. These data show that compared with CD 28, co‐stimulation through the NKG 2D receptor leads to the differential activation of the mTOR signalling pathway and potentially supports memory CD 8 + T‐cell differentiation.