Unknown,Transcriptomics,Genomics,Proteomics

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Neonatal naïve CD8+ T cells have effector-like gene expression that prevents memory cell formation [human miRNA-seq]

ABSTRACT: Neonates are intrinsically defective at creating memory CD8+ T cells in response to infection with intracellular pathogens. Here we investigated differential of small RNAs, transcription factors, and chemokine receptors regulation in neonates as compared to adults before and during infection. We found that prior to infection, naïve cells have a different expression profile for many microRNAs, and gene targets of these microRNAs show widespread expression differences. These targets and other changes in gene expression in naïve cells result in neonatal cells that get activated more easily, express chemokine receptors that home to sites of infection, and are less protected from apoptosis during contraction. As a result, changes in neonatal naïve cells drive effector cell terminal differentiation at the expense of creating long-lived memory cells. Small RNAs were sequenced from adult and neonatal CD8+ T cells before infection.

ORGANISM(S): Homo sapiens

SUBMITTER: Andrew Grimson

PROVIDER: E-GEOD-66650 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Neonates are highly susceptible to repeat infection and respond poorly to vaccination; these attributes derive from intrinsic differences between neonatal and adult naïve CD8+ T cells. In contrast to adult cells, naïve neonatal cells exhibit a greatly limited ability to differentiate into memory cells, a fundamental property of their adult counterparts. Here, we describe the role of the miR-29 microRNA in naïve T cells, focusing on age-related differences in miR-29 expression and the consequences of these differences in adult and neonatal cells, from mice and humans. In adults, high expression of miR-29 licenses naïve cells towards eventual memory cell fates; whereas neonatal naïve cells, which lack high expression of miR-29, are predisposed towards effector cell fates in response to an infection. Multiple lines of evidence support this model, including analysis of a mouse model deficient in miR-29, which we examine with adoptive transfer experiments to define the functional consequences of reduction of miR-29, together with genomic assays to define the regulatory impact of miR-29. Adult miR 29 deficient naïve CD8+ T cells cell are primed for activation and therefore secrete elevated levels of cytolytic molecules, and express transcription factors at levels associated with effector cell differentiation; moreover, these cells exhibit an altered CD8+ T cell memory repertoire, akin to that of neonatal CD8+ T cells. Importantly, we use a method that exploits extracellular vesicles as a delivery vehicle with which to modulate levels of miR-29 in neonatal and adult naïve T cells, examining both human and mouse cells. For example, increasing miR 29 expression in mouse naïve neonatal CD8+ T cells significantly improved the memory response during infection, concomitant with alterations to the chromatin landscape characteristic of cells primed for memory differentiation. Delivery of miR-29 antagomirs to human adult naïve CD8+ T cells was sufficient to induce the adult cells to adopt phenotypes and gene expression signatures normally found in cells present in newborns. This study establishes miR-29 as a key conserved regulator in naïve CD8+ T cells, and by adjusting levels of miR-29, has the potential to underlie therapeutic strategies for controlling the balance of effector versus memory fates in human T cells.

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Neonatal naïve CD8+ T cells have effector-like gene expression that prevents memory cell formation [human miRNA-seq]

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