Project Summary / Abstract Though CD8+ T cell-based immunotherapies have revolutionized treatment for hematologic cancers and chronic viral infections, T cell exhaustion remains a barrier to fully realizing their therapeutic potential. T cell exhaustion is the hierarchical loss of proliferation, cytokine production, and effector function of CD8+ T cells after chronic antigen stimulation. Not every T cell becomes exhausted to the same degree or at the same rate, but the factors governing heterogeneity in susceptibility to exhaustion are undefined. The Rudd lab was the first to show that a previously-overlooked source of heterogeneity within the naïve CD8+ T cell pool—developmental origin—is deterministic in a CD8+ T cell’s fate after acute infection. We believe that developmental origin is also consequential in chronic infection, for our preliminary data shows that neonatal CD8+ T cells (derived from the fetal liver) are resistant to phenotypic and functional exhaustion, whereas adult cells (derived from adult bone marrow) are more susceptible. We also showed that overexpressing Lin28b, an oncofetal RNA-binding protein that negatively regulates let-7 microRNAs and is only expressed in fetal liver HSCs, is sufficient to convert the adult phenotype to the neonatal one. Our objective is therefore to dissect the developmentally-regulated programs underlying differential responses to chronic stimulation. We will use innovative approaches to test our hypothesis that adult CD8+ T cells are more susceptible to exhaustion than neonatal cells due to age-related differences in let-7/Lin28b expression that program metabolism away from aerobic glycolysis. In Aim 1, we will determine how developmental origin and Lin28b expression impact propensity for CD8+ T cell exhaustion. Results from this aim will make clear how distinct subsets of exhausted cells arise among differently-aged CD8+ T cells, and shed light on whether developmental pathways protect against irreversible exhaustion. In Aim 2, we will determine how Lin28b-mediated metabolic programs underlie differently-aged cells’ susceptibility to become exhausted. These results will provide a mechanistic explanation for how developmental imprinting affects T cell exhaustion dynamics. By investigating the developmentally-distinct CD8+ T cell response to chronic infection, and the role that let-7, Lin28b, and metabolic programing play in said response, this proposal will uncover a previously-unexplored factor in determining T cell exhaustion. Because developmentally-ingrained pathways are common to all T cells, understanding these pathways—and finding strategies to fine-tune them—will have wide- reaching implications for neonatal disease, chronic infection, and cancer alike.

Project Narrative Neonates respond differently to chronic infection than adults, and we have shown that a possible reason is their underlying resistance to CD8+ T cell exhaustion. This proposal will identify the key gene regulatory pathways and metabolic factors that contribute to these age-related differences, allowing us to develop more effective strategies to protect individuals from chronic infections and cancer alike.