RT Journal Article SR Electronic T1 DOK1 and DOK2 regulate CD8+ T cell signaling and memory formation without affecting tumor cell killing JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.12.17.473111 DO 10.1101/2021.12.17.473111 A1 V. Laletin A1 P.-L. Bernard A1 C. Montersino A1 Y. Yamanashi A1 D. Olive A1 R. Castellano A1 G. Guittard A1 J. A. Nunès YR 2021 UL http://biorxiv.org/content/early/2021/12/19/2021.12.17.473111.abstract AB 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.Competing Interest StatementD.O. is a cofounder of Imcheck Therapeutics, Alderaan Biotechnology and Emergence Therapeutics. The other authors declare no competing financial interests.