DOK1 and DOK2 regulate CD8 + T cell signaling and memory formation without affecting tumor cell killing
Abstract
ABSTRACT Targeting intracellular inhibiting proteins is a promising strategy to improve CD8 + T cell anti-tumor efficacy. DOK1 and DOK2 are CD8 + T cell inhibitory proteins that are targeted in this study in order to improve the activation and cytotoxic capacities of these cells. To evaluate the role of DOK-1 and DOK-2 depletion in physiology and effector function of T CD8 + lymphocyte and in cancer progression, a transgenic T cell receptor mouse model specific to melanoma antigen hgp100 (pmel-1 TCR Tg) was established. Depletion of both Dok1 and Dok2 did not affect the development, proliferation, mortality, activation and cytotoxic function of naive CD8 + T cells. However, after an in vitro pre-stimulation Dok1 / Dok2 DKO CD8 + T cells had higher percentage of effector memory T cells and showed an increase in levels of pAKT and pERK upon TCR stimulation. Despite this improved TCR signaling, pre-stimulated Dok1 / Dok2 DKO CD8 + T cells did not show any increase in their activation or cytotoxicity capacities against melanoma cell line expressing hgp100 in vitro . Altogether we demonstrate here a novel aspect of the negative regulation by DOK1 and DOK2 proteins in CD8 + T cells. In conclusion, DOK1 and DOK2 have an inhibitory role following long term T cell stimulations.