PD-1 aborts the activation trajectory of autoreactive CD8+ T cells to prohibit their acquisition of effector functions.

PD-1 aborts the activation trajectory of autoreactive CD8+ T cells to prohibit their acquisition of effector functions. J Autoimmun. 2019 Jul 02;: Authors: Okamura H, Okazaki IM, Shimizu K, Maruhashi T, Sugiura D, Mizuno R, Okazaki T Abstract Anti-PD-1 therapy can induce eradication of tumors and immune-related adverse events (irAEs) in humans and model animals. However, how anti-PD-1 therapy modifies cellular phenotypes of CD8+ T cells to destroy tumors and damage self-tissues remains to be clarified. Here we performed single cell mRNA expression profiling of autoreactive CD8+ T cells under or beyond PD-1 suppression in target tissues and reconstructed their activation trajectory. Autoreactive CD8+ T cells went through four activation phases and PD-1 strongly attenuated the transition from the second- to the third-phase, where effector functions were acquired. Shifts in cluster composition of autoreactive CD8+ T cells markedly reflected the severity of autoimmunity. In addition, genes up-regulated along the activation-trajectory in autoimmunity were highly expressed in responders of melanoma patients in anti-PD-1 therapy, suggesting that tumor-specific T cells need to be activated in a similar trajectory to destroy tumors in human patients upon PD-1 blockade. These findings reveal that PD-1 blockade facilitates the activation trajectory of CD8+ T cells to boost their effector functions. Targeted manipulation of the trajectory could ...
Source: Journal of Autoimmunity - Category: Allergy & Immunology Authors: Tags: J Autoimmun Source Type: research