CHARACTERIZATION OF EARLY CD8 T CELL RESPONSES AFTER BYSTANDER AND ANTIGEN-SPECIFIC ACTIVATION

Abstract

In light of the recent COVID-19 pandemic, it has become imperative to understand how CD8 T cells, an important line of defense in the adaptive immune system, are activated in response to virus infections and other diseases. Although past work informs our understanding about the biology of CD8 T cell response at the later stages of the adaptive immunity (usually 5-7 days post initiation), only scanty information is available about the events that shape CD8 T cell activation during the early time points (0-3 days post initiation). To address this knowledge gap, this study investigated the early events that characterize CD8 T cell activation. In the first part of this work, we focused on bystander activation of CD8 T cells. Here, we studied how naïve CD8 T cells are activated in a bystander manner within 24 hours of exposure to virus. We elucidated the role of type 1 interferons and STAT1 in this bystander activation of naïve CD8 T cells and further demonstrated that metabolic reprogramming occurs in these cells at this early time point. We additionally discovered a role for NAD+ salvage metabolism in the bystander induction of naïve CD8 T cells. This study provided novel insight into the early events that impact the biology of naïve CD8 T cells after virus exposure and will serve to guide better development of anti-viral treatments and vaccines that rely on effective CD8 T cell activation. In the second part of this study, we focused on a poorly characterized CD8 T cell subset identified as CD44lowCD62Llow CD8 T cells. We first discovered that CD44lowCD62Llow CD8 T cells are induced as early as 1 hour after antigen-specific stimulation. We demonstrated that the CD44lowCD62Llow CD8 T cells were capable of functional activity via IFN-γ production as early as 6 hours after stimulation and that type 1 interferons drove increased functional capacity of these cells. Further, we revealed that these early CD44lowCD62Llow CD8 T cells were metabolically unique when compared to the other naïve, effector and memory CD8 T cell subsets. Our analyses uncovered a role for aminoacyl tRNA biosynthesis in the metabolism of CD44lowCD62Llow T cells and overall, our studies support the model that naïve CD8 T cells differentiate to this unique phenotype-CD44lowCD62Llow-a transition state induced prior to effector or memory differentiation. This previously unreported, very early differentiation event provides invaluable insight into antigen-driven early CD8 T cell activation and will be critical for future studies aiming to study/harness CD8 T cells for treatment across multiple disease areas.