We recently developed a novel fate-mapping strategy to ‘timestamp’ CD8+ T cells at various stages of development and examined their phenotype and behavior in adulthood. We found that the developmental origin of naïve CD8+ T cells plays a deterministic role in their fate after infection in adults, and the CD8+ T cells produced early in life are the first cells to respond, rapidly becoming terminally differentiated during infection. These data demonstrate that developmental layers exist in the CD8+ T cell response to infection, and that the heterogeneity in the effector pool is linked to variation in the developmental origins of the responding cells. In the future, we plan to explore how environmental factors (diet, chronic infections, microbiome) alter the developmental layering of the T cell pool during immune ontogeny and contribute to variation in the host response to infection during adulthood.
In healthy adults, viral and intracellular bacterial infections result in the formation of memory T cells, which protect the host from repeat infections. However, neonates and infants have an impaired ability to develop memory T cells for reasons that have remained unclear. We recently discovered that neonatal CD8+ T cells are inherently biased in becoming short-lived effector cells, whereas adults give rise to more memory cells after infection. We also found that cell intrinsic differences between neonatal and adult CD8+ T cells are largely due to their derivation from distinct pools of hematopoietic stem cells (fetal liver vs. adult bone marrow). Our current work seeks to uncover the key gene regulatory and metabolic networks that underlie age-related differences in CD8+ T cells, allowing us to develop more rational therapeutic strategies for enhancing immunity in early life.
MicroRNAs (miRNAs) are short non-coding RNAs, which operate by reducing the expression of specific genes. Since miRNAs are developmentally regulated and required for CD8+ T cell function, we hypothesize that defective CD8+ T cell memory formation in early life is due to differences in miRNA expression patterns between neonatal and adult CD8+ T cells. To test our hypothesis, we have teamed up with Andrew Grimson’s lab and used next generation sequencing to identify miRNAs that are differentially regulated in different-aged CD8+ T cells from mice and humans. We are now performing a wide range of studies to understand how age-related changes in certain miRNAs alter the ability of CD8+ T cells to respond to infection and develop into memory cells. We are also working with collaborators at the University of Rochester and the Malawi-Liverpool School of Tropical Medicine to determine whether microRNAs can predict a vaccine-specific CD8+ T cell response in newborns. These studies are expected to uncover new biomarkers for predicting the effectiveness of vaccines and novel therapeutic strategies for enhancing immunity in early life.