Wednesday, February 5, 2025
2/5/2025
ABSTRACT T cell exhaustion is a differentiation state that is marked by the loss of effector function and increased expression of inhibitory receptors such as PD-1. Although virus-specific CD8 T cells are commonly considered as a homogeneous population that gradually become exhausted over time, recent research has clearly demonstrated that a CXCR5hi TCF-1hi subset is serving as a self-renewing progenitor population that can give rise to a more terminally exhausted CXCR5lo TCF-1lo subset. To better dissect the heterogeneity of “exhausted” CD8 T cells, the lab applied single cell RNA-seq (scRNA-seq) to the chronic LCMV infection and identified three major subsets of virus-specific CD8 T cells that are phenotypically, functionally and transcriptionally distinct. Not only had the lab validated the existence of these subsets of T cells experimentally by flow cytometry, more advanced computational analyses were also performed to further predict their core transcriptional networks and developmental trajectories. Collectively, the findings reveal that a TCF-1hi progenitor subset can give rise to either a truly exhausted PD-1hi subset or a newly identified functional effector population that is named CX3CR1hi subset. This discovery laid a solid framework that allows testing of how extracellular signals and intrinsic genetic circuits regulate the formation and function of these three subsets of CD8 T cells. More importantly, it provides unprecedented opportunities to explore the possibility of generating more functional CX3CR1hi cells from TCF-1hi progenitors to overcome T cell exhaustion. This conceptual breakthrough is obviously applicable to control over chronic viral infection as well as cancer. Intriguingly, the preliminary study has also demonstrated that CD4 helper T cells, possibly through producing IL-21, are critical for TCF-1hi CX3CR1hi transition. This led to the hypothesis that inflammatory cytokines (such as CD4- derived IL-21) modulate the cellular, functional and transcriptional diversity of virus-specific CD8 T cells during chronic LCMV infection. Blocking antibodies, RNA interference and genetic deletion models will be used to further dissect how inflammatory cytokines and transcriptional networks regulate heterogeneity in T cell exhaustion. Furthermore, the lab proposes to redirect CD8 T cell differentiation away from “exhaustion” by providing additional “CD4 help”, either alone or in combination with PD-1 blockade. The lab will test if providing IL-21 producing CD4 T cells through adoptive transfer could drive TCF-1hi progenitor cell differentiation into functional CX3CR1hi effector cells. Overall, knowledge gained from this research will provide mechanistic insights into how to redirect the formation of functional effector T cells and simultaneously limit T cell exhaustion for improved viral control over chronic infection.
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).