The influence of environmental cues on CD8⁺ T cell function and metabolism

• Main Author: Carrasco Hope, Helen
• Format: Dissertation
• Language: English
• Published: University of Leeds 2021

CD8⁺ T lymphocytes play a critical role in our protection against pathogens and tumours. CD8⁺ T cell function is shaped by a myriad of environmental cues that include TCR-stimulation, co-stimuli, pro- and anti-inflammatory cytokines and nutrient availability. Understanding how CD8⁺ T cells integrate these signals and how they influence T cell output is crucial to better comprehend immune regulation and to find novel targets for immunotherapy. During the last decade, it has become more evident that T cell metabolism tightly controls T cell fate. This principle has provided a novel signalling network that can be manipulated in order to modulate T cell responses but that still needs to be fully explored. In this thesis, I determine the impact of several environmental cues on CD8⁺ T cell activation and metabolism. First, the study of signal 1 (TCR- triggering), signal 2 (CD28) and signal 3 (IL-12 or IFNα) revealed that these cooperate to induce a full T cell activation state, contributing separately to T cell functionality and metabolism. Second, the study of the anti-inflammatory cytokine TGFβ established that its effect on the suppression of CD8⁺ T cell activation is predominantly mediated by the repression of Myc, ultimately impeding TCR- driven metabolic reprogramming. Finally, the study of asparagine (Asn) deprivation showed that CD8⁺ T cells require the supplementation of this amino acid during early stages of T cell activation, but lose this requirement upon upregulation of the enzyme asparagine synthetase (ASNS). These findings demonstrate that modulation of T cell responses by environmental cues are linked to the regulation of metabolic pathways and shed light into new mechanisms that might be exploited to finely tune T cell function.