Following infection, a small percentage of effector CD8+ T cells survive and transition into the long-lived memory pool. Given that memory CD8+ T cells are key to immunity against intracellular pathogens, it is essential that we understand the mechanisms by which they are formed. This question has been at the forefront of the field for decades. The current dogma suggests that a single lineage of nave T cells can give rise to different short- and long-lived subsets of effector or memory T cells, depending upon the cues (inflammation, antigen) they encounter during infection. However, in the last funding cycle, we discovered that the propensity for T cells to adopt particular fates during infection is, instead, pre-programmed prior to infection, and is largely determined by their developmental origin. As all of our work to date has been performed in the context of acute infections, the major goal of our renewal proposal is to extend our studies to chronic infection, where we will determine how heterogeneity within the memory pool is linked to variation in the developmental origins of the responding cells. To accomplish this goal, we will combine our novel fate mapping system with the well-characterized mouse model of LCMV infection to dissect the functional heterogeneity within the memory pool. Our preliminary studies indicate that adult-derived cells preferentially become functionally exhausted during chronic infection compared to fetal-derived cells. However, clonal exhaustion of adult-derived CD8+ T cells can be prevented by overexpression of Lin28b, a master regulator of fetal-derived immune cells. Based on these findings and our published work, we hypothesize that the fate of CD8+ T cells during chronic infection is linked to their developmental origin. In the first aim, we will determine how developmental origin alters the CD8+ T cell response to chronic pathogens. In the second aim, we will examine how developmental origin alters gene regulatory programs in CD8+ T cells during chronic infection. In the last aim, we will determine how developmental differences in Lin28b influence the ability of CD8+ T cells to respond to chronic infection. Knowledge gained from these studies is expected to provide a better understanding of the mechanisms regulating the CD8+ T cell response to chronic pathogens, which is essential for developing more precise and effective strategies to restore functionality in exhausted CD8+ T cells.
The CD8+ T cell response to chronic pathogens is often ineffective due to functional exhaustion of the responding cells. This grant aims to identify the key mechanisms that underlie these impairments, allowing us to develop more precise immunotherapies to restore immune function in exhausted CD8+ T cells.
|Jurkowska, Halina; Niewiadomski, Julie; Hirschberger, Lawrence L et al. (2016) Downregulation of hepatic betaine:homocysteine methyltransferase (BHMT) expression in taurine-deficient mice is reversed by taurine supplementation in vivo. Amino Acids 48:665-676|
|Wang, Jocelyn; Wissink, Erin M; Watson, Neva B et al. (2016) Fetal and adult progenitors give rise to unique populations of CD8+ T cells. Blood 128:3073-3082|
|Reynaldi, Arnold; Smith, Norah L; Schlub, Timothy E et al. (2016) Modeling the dynamics of neonatal CD8+ T-cell responses. Immunol Cell Biol 94:838-848|
|Smith, Norah L; Wissink, Erin M; Grimson, Andrew et al. (2015) miR-150 Regulates Differentiation and Cytolytic Effector Function in CD8+ T cells. Sci Rep 5:16399|
|Mentch, Samantha J; Mehrmohamadi, Mahya; Huang, Lei et al. (2015) Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism. Cell Metab 22:861-73|
|Madhukar, Neel S; Warmoes, Marc O; Locasale, Jason W (2015) Organization of enzyme concentration across the metabolic network in cancer cells. PLoS One 10:e0117131|
|Wissink, Erin M; Smith, Norah L; Spektor, Roman et al. (2015) MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells. Genetics 201:1017-30|
|Block, Keith I; Gyllenhaal, Charlotte; Lowe, Leroy et al. (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35 Suppl:S276-S304|
|Barker, Brandon E; Sadagopan, Narayanan; Wang, Yiping et al. (2015) A robust and efficient method for estimating enzyme complex abundance and metabolic flux from expression data. Comput Biol Chem 59 Pt B:98-112|
|Ser, Zheng; Liu, Xiaojing; Tang, Ngoc Nu et al. (2015) Extraction parameters for metabolomics from cultured cells. Anal Biochem 475:22-8|
Showing the most recent 10 out of 19 publications