Neonatal naive CD4+ T cells have increased calcium flux and higher expression of miR-181a relative to adult naive CD4+ T cells (153.39)

Abstract

Abstract Neonates are highly susceptible to severe infection by a variety of intracellular pathogens, including M. tuberculosis and T. gondii. A large body of evidence suggests that a limitation in T helper 1 (Th1) responses accounts for much of this susceptibility. Our lab has previously defined a number of limitations in neonatal naive CD4+ T cells obtained from umbilical cord blood that restrict Th1 generation in vitro. These include decreased expression by naive CD4+ T cells of CD40 ligand and IFN-γ. Unexpectedly, we have also observed increased calcium flux in neonatal cells in response to CD3 mAb cross-linking. Because of the diverse molecular differences between neonatal and adult naive CD4+ T cells, we investigated differences in microRNA expression. miR-181a, which has been shown to regulate calcium flux positively in murine T cells, was expressed at higher levels in neonatal naive CD4+ T cells, consistent with increased calcium flux. Its predicted mRNA targets are expressed at lower levels in neonatal naive CD4+ T cells by gene set enrichment analysis (GSEA). Others have shown that over-expression of miR-181a results in increased phosphorylation of Erk1/2 after CD3 mAb crosslinking, and we are examining the activity of the Erk pathway in neonatal and adult naive CD4+ T cells. Also in progress are studies using a stable, lentiviral system to determine the effects of miR-181a over-expression and knockdown in human CD4 T cells focusing on validated murine mRNA targets.