Abstract A05: NKG2D and CD28 receptors differentially activate mTOR to alter murine effector CD8+ T cell differentiation

Abstract

Abstract Memory CD8+ T cells are an essential component of anti-tumor and anti-viral immunity. Activation of the mammalian/mechanistic target of rapamycin (mTOR) pathway has been implicated in regulating the differentiation of effector and memory T cells. However, the mechanisms that control mTOR activity during immunity to tumors and infections are not well known. Activation of costimulatory receptors, including CD28 and NKG2D, activate PI3K and subsequently may activate the mTOR pathway in CD8+ T cells. Therefore this study compared the activation of the mTOR signaling pathway after costimulation through CD28 or NKG2D receptors in murine effector CD8+ T cells. Compared to CD28 costimulation, activation through CD3 and NKG2D receptors had weaker activation of mTORc1 as shown by decreased phosphorylation of mTORc1 targets S6K1, ribosomal protein S6, and 4EBP-1. NKG2D costimulation also showed increased gene expression of TSC2, a negative regulator of mTORc1, whereas CD28 costimulation increased gene expression of Rheb, an activator of mTORc1, and HIF-1α and VEGFα, pro-angiogenic factors downstream of mTORc1. Strong mTORc1 activation in CD28-costimulated cells also increased expression of transcription factors that support effector cell differentiation, namely T-bet, and BLIMP1, whereas low levels of mTORc1 activation allowed for the expression of Eomes and BCL6 during NKG2D stimulation, and increased expression of central memory markers CD62L and CD127. These data show that compared to CD28, costimulation through the NKG2D receptor leads to the differential activation of the mTOR signaling pathway and potentially supports memory CD8+ T cell differentiation. Citation Format: Bryan McQueen, Kelsey Trace, Emily Whitman, Amorette Barber. NKG2D and CD28 receptors differentially activate mTOR to alter murine effector CD8+ T cell differentiation. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A05.