Neonates are highly susceptible to intracellular pathogens and develop poor immunity to infection. Since immunity against these infectious agents is largely dependent upon memory CD8+ T cells, we have performed detailed analysis of the CD8+ T cell response in early life and found that neonatal CD8+ T cells are intrinsically defective at differentiating into memory CD8+ T cells. Surprisingly, impaired memory formation by neonatal CD8+ T cells was not due to an inability to respond, rather neonatal CD8+ T cells proliferated more rapidly than adult cells and quickly became terminally differentiated. One of the most ancient and conserved regulators of proliferation and differentiation during early stages of development is the let-7 miRNA family. Let- 7 represses cell proliferation and growth by targeting many metabolic genes, cell cycle factors and oncogenes for repression. While let-7 is expressed at high levels in adult CD8+ T cells, its expression is blocked by Lin28b in neonatal CD8+ T cells, creating a genomic landscape that is highly conducive for rapid proliferation. Therefore, we believe that neonatal CD8+ T cells become more terminally differentiated and form poor memory cells, because of an inability to repress major transcriptional and metabolic pathways via let-7. Our proposal will test the hypothesis that different genetic programs, regulated by the let-7/Lin28b axis, alter the generation and maintenance of memory CD8+ T cells following neonatal infection. In the first aim (SA1), we will adjust expression levels of let7 and Lin28b in different aged CD8+ T cells and determine their role in neonatal and adult memory CD8+ T cell formation. In the last 2 aims (SA2 and SA3), we will identify the key transcription factors and metabolic pathways that are regulated by let-7/Lin28b and contributing to impaired development of memory CD8+ T cells in early life. Upon completion of this work, we will have obtained a complete mechanistic understanding of why neonatal CD8+ T cells fail to differentiate into memory and know whether correcting transcriptional and metabolic differences can restore protective immunity in early life. Our focus on let-7/Lin28b, which appears to regulate these differences, will allow us to manipulate the number and type of memory CD8+ T cells that are generated in specific ways. This is a novel and targeted approach to enhance memory T cell development in early life.
Neonates respond poorly to vaccination and secondary infections, resulting in increased morbidity and mortality. This proposal will identify the key gen regulatory and metabolic networks that underlie these impairments, allowing us to develop more rational therapeutic strategies for enhancing immunity in early life.
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