Friday, May 3, 2024
5/3/2024
ABSTRACT Quiescent TCF1Hi stem-like CD8 T cells – functionally poised to rapidly expand and mount a vigorous anti-viral immune response – are critical for mediating effective viral control while avoiding immunopathology during chronic viral infections. The phenotypic, functional and molecular features of TCF1Hi stem-like CD8 T cells are well characterized. However, very little is known about the precise signals that drive their generation. The overarching goals of this proposal are to (i) define how the long-term pool of TCF1Hi stem-like anti-viral CD8 T cells is generated during chronic viral infections, and (ii) leverage this knowledge for devising strategies to engineer conceptually novel checkpoint blockade and adoptive cell transfer therapies in situations where viral/antigen persistence drives functional exhaustion and loss of host immunity. This proposal is founded on newly published and unpublished findings from our team showing a critical and unexpected role of tempered IL-2 signals in the development of TCF1Hi stem-like CD8 T cells during chronic viral infection. Our preliminary studies further show that IL-2 production by virus-specific CD8 T cells is inversely related to PD-1 signals during priming. Additionally, we and others have shown that loss of PD-1 signals leads to metabolic dysregulation and impaired survival of antiviral CD8 T cells that are key to long-term viral control. Collectively, these findings present a unique role of the PD-1/IL-2 nexus during early T cell priming, in programming the development of TCF1Hi stem-like CD8 T cells, for long-term maintenance of host anti-viral responses. We hypothesize that PD-1-driven regulation of IL-2 production during priming promotes the development of stem-like quiescent CD8 T cells. We further propose that mechanisms that promote inhibitory PD-1 signals and temper IL-2 signals to CD8 T cells, during early T cell priming and initiation of anti-viral host immune responses, would lead to the generation of TCF1Hi stem-like CD8 T cells with enhanced potential for functional rejuvenation and viral control in response to checkpoint blockade. We will engage high dimensional single cell transcriptomic, metabolomic and proteomic tools along with leading edge RNP-based in vivo Crispr/Cas9 technology and conditional gene ablation models to: (1) Dissect the programming of TCF1Hi stem-like CD8 T cells during early stages of chronic viral infections through the PD- 1-driven IL-2 regulatory axis. (2) Explore novel preconditioning strategies to enhance TCF1Hi stem-like cells during established chronic viral infections for improved PD-1 checkpoint blockade through g-chain cytokines. (3) Establish the relationship between IL-2 signaling signatures and stem-like T cells, vis a vis clinical outcomes of checkpoint blockade, for Polyoma virus-specific exhausted CD8 T cells in human patient samples. Successful completion of these studies will provide fundamental insight into the ontogeny of stem-like TCF1Hi cells, alongside translational advances into discovery of newer druggable targets for improved control of chronic viral infections.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
