Contribution of ROS and metabolic status to neonatal and adult CD8+ T cell activation.

José Antonio Sánchez-Villanueva,Otoniel Rodríguez-Jorge,Aurélien Naldi,María Angélica Santana,Oscar Ramírez-Pliego,Gabriela Rosas Salgado,Denis Thieffry,Céline Hernandez,Wassim Abou-Jaoudé

doi:10.1371/journal.pone.0226388

Abstract

In neonatal T cells, a low response to infection contributes to a high incidence of morbidity and mortality of neonates. Here we have evaluated the impact of the cytoplasmic and mitochondrial levels of Reactive Oxygen Species of adult and neonatal CD8+ T cells on their activation potential. We have also constructed a logical model connecting metabolism and ROS with T cell signaling. Our model indicates the interplay between antigen recognition, ROS and metabolic status in T cell responses. This model displays alternative stable states corresponding to different cell fates, i.e. quiescent, activated and anergic states, depending on ROS levels. Stochastic simulations with this model further indicate that differences in ROS status at the cell population level contribute to the lower activation rate of neonatal, compared to adult, CD8+ T cells upon TCR engagement. These results are relevant for neonatal health care. Our model can serve to analyze the impact of metabolic shift during cancer in which, similar to neonatal cells, a high glycolytic rate and low concentrations of glutamine and arginine promote tumor tolerance.

Highlights

Infections in children under six months cause approximately four million deaths per year [1]
We quantified the percentage of cells in the high or low mROS gates from neonatal or adult CD8+ T cells
We found that neonatal cells have a higher percentage of cells with high mROS, whereas adult cells are more frequent in the low mROS gate (Fig 1D)

Summary

Introduction

Infections in children under six months cause approximately four million deaths per year [1]. Our results suggest fundamental differences in the ROS signaling and redox status between CD8+ T cells from newborns and adults. Using a logical formalism implemented in the software GINsim ([24] http://ginsim.org), we defined a comprehensive dynamical model integrating the most relevant signaling, metabolic and transcriptional regulatory components controlling the activation of CD8+ T lymphocytes. This model displays alternative stable states, which corresponds to different cell fates, i.e. quiescence, activation and anergy, depending on ROS status. Stochastic simulations further suggest that the lower activation rate of neonatal compared to adult CD8+ T cells upon TCR engagement is attributable to differences in ROS status or glutaminolysis at the cell population level

Ethics statement

Results

Discussion