Human Neonatal Naive CD4+ T Cells Have Enhanced Activation-Dependent Signaling Regulated by the MicroRNA miR-181a

Abstract

Human neonates have reduced and delayed CD4+ T-cell immunity to certain pathogens compared to older children and adults, but the mechanisms for these developmental differences in immune function remain poorly understood. We investigated the hypothesis that impaired human neonatal CD4+ T-cell immunity was due to reduced signaling by naive CD4+ T cells following engagement of the αβ-TCR/CD3 complex and CD28. Surprisingly, calcium flux following engagement of CD3 was significantly higher in neonatal naive CD4+ T cells from umbilical cord blood compared to naive CD4+ T cells from adult peripheral blood. Enhanced calcium flux was also observed in adult CD4+ recent thymic emigrants. Neonatal naive CD4+ T cells also had higher activation-induced Erk phosphorylation. The microRNA miR-181a, which enhances activation-induced calcium flux in murine thymocytes, was expressed at significantly higher levels in cord blood naive CD4+ T cells compared to adult cells. Overexpression of miR-181a in adult naive CD4+ T cells increased activation-induced calcium flux, implying that the increased miR-181a levels of cord blood naive CD4+ T cells contributed to their enhanced signaling. In contrast, AP-1-dependent transcription, which is downstream of Erk and required for full T-cell activation, was decreased in cord blood naive CD4+ T cells compared to adult cells. Thus, cord blood naive CD4+ T cells have enhanced activation-dependent calcium flux, indicative of the retention of a thymocyte-like phenotype. Enhanced calcium signaling and Erk phosphorylation are decoupled from downstream AP-1-dependent transcription, which is reduced and likely contributes to limitations of human fetal and neonatal CD4+ T-cell immunity.

Challenges in vaccination of neonates, infants and young children

“…Impairment of CD4 T-cell activation could be due to a defect in the TCR signaling pathway that activates protein phosphorylation and activation of phospholipases[71]. Experiments with umbilical cord blood T-cells have shown that antigen stimulation does not influence TCR-CD3 surface expression, but initializes TCR internalization and downstream signaling including activation of phospholipase C-γ (PLC) by Src family kinases, Syk, Lck, ZAP70 and Fyn[72].…”

Helper T Cell Plasticity: Impact of Extrinsic and Intrinsic Signals on Transcriptomes and Epigenomes

“…Mir-181a is also important in the peripheral CD4 + T cell response. Expression of miR-181a is high in human neonatal naïve CD4 + T cells, and age-associated decrease of miR-181a increased DUSP6 expression, and diminished ERK phosphorylation via TCR stimulation (Palin et al 2013). Reconstitution of miR-181a lowered DUSP6 expression, and restored CD4 + T cell responses (Li et al 2012).…”

ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells

“…2). The link between miR-181a expression and modulation of ERK phosphorylation through the regulation of phosphatases is well established in a number of experimental systems 11,15,[19][20][21][22] . We therefore analysed the expression of DUSP5 and DUSP6, two ERK-specific phosphatases acting in the nucleus and cytoplasm, respectively 23 , and also of the phosphatase PTPN11 (SHP-2), which are all validated direct targets of miR-181a (ref.…”