Abstract 1269: Activation of the NKG2D receptor differentially activates mTOR and NFκB signaling pathways in CD8+ T cells.

Abstract

To induce strong anti-tumor immune responses, CD8+ T cells require stimulation through the TCR and costimulatory receptors. Each costimulatory molecule can have a unique effect on the function of T cells due to differential activation of downstream signaling pathways and gene expression. One costimulation molecule that is likely to be engaged in the tumor microenvironment is NKG2D since the ligands for this receptor are expressed in over 80% of tumors. In order to determine how activation of costimulatory receptors in the tumor microenvironment affects CD8+ T cell functions, previous studies have compared the activation of CD8+ T cells through CD3 in combination with either CD28 or NKG2D and showed that CD3 and NKG2D stimulated cells secreted less anti-inflammatory cytokines. Both costimulatory receptors activated AKT, however the altered cytokine secretion was due to the unique activation of β-catenin in NKG2D stimulated cells. This study aimed to further investigate the differences in the signaling pathways downstream of AKT that are activated by CD3 /CD28 and CD3/NKG2D. Specifically, this study focused on the activation of mammalian target of rapamycin complex 1 and 2 (mTORC1 and mTORC2) along with nuclear factor kappa B (NFκB), all of which have been shown to have important roles in the CD8+ T cell anti-tumor functions. Activation of the mTORC1, mTORC2 and NFκB pathways were compared in murine CD8+ effector T cells stimulated through CD3 alone, CD3 and CD28 or CD3 and NKG2D. The activation of mTORC1was measured through phosphorylation of its downstream effectors including 4-EBP1, P70SK6 and HIF-1, while mTORC2 measured activation of AKT, SGK1 and NFkβ. Activation of CD8+ T cells through CD3 and NKG2D decreased activation of mTORC1 while increasing activation of mTORC2. Together this shows that activation through NKG2D leads to the differential activation of signaling pathways, thus likely altering the anti-tumor effector functions of the CD8+ T cells. Citation Format: Amorette E. Barber, Taylor Bedsworth, Jasmine Spence, Emily Whitman. Activation of the NKG2D receptor differentially activates mTOR and NFκB signaling pathways in CD8+ T cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1269. doi:10.1158/1538-7445.AM2013-1269