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bioRxiv · 10.1101/2021.12.17.473111

DOK1 and DOK2 regulate CD8+ T cell signaling and memory formation without affecting tumor cell killing

Laletin, V.·Bernard, P.-L.·Camille, M.·Yamanashi, Y.·Olive, D.·Castellano, R.·Guittard, G.·Nunes, J.
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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.

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Laletin, V., Bernard, P.-L., Camille, M., Yamanashi, Y., Olive, D., Castellano, R., Guittard, G., Nunes, J.. 2021-12-19. DOK1 and DOK2 regulate CD8+ T cell signaling and memory formation without affecting tumor cell killing. https://doi.org/10.1101/2021.12.17.473111

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