Decreased CD154 expression by neonatal CD4+ T cells is due to limitations in both proximal and distal events of T cell activation

Abstract

Neonatal CD4(+) T cells express less CD154 protein and mRNA than adult CD4(+) T cells after activation by calcium ionophore and phorbol ester, but the mechanism for this reduced expression and its relevance to the primary immune response remain unclear. We compared expression of CD154 protein and mRNA and CD154 gene promoter activity by purified naive (CD45RA(high)CD45RO(low)) neonatal and adult CD4(+) T cells after activation by calcium ionophore (ionomycin) and phorbol myristate acetate (PMA) treatment or by engagement of alphabeta TCR-CD3 complex. Substantial and consistent reductions in expression by neonatal cells were found in all cases and were paralleled by decreased CD154-dependent activation of a B cell line. CD69 expression by neonatal CD4(+) T cells after alphabeta TCR-CD3 engagement was also reduced compared to adult cells, which suggested that limitations in activation-induced signaling by neonatal CD4(+) T cells occurred at a point upstream of where the signaling pathways leading to CD154 and CD69 expression diverge. Decreased CD154 expression by neonatal cells after alphabeta TCR-CD3 engagement was paralleled by a lower free intracellular calcium concentration, a key event for CD154 gene transcription. Reduced CD154 promoter activity by neonatal cells persisted when proximal signaling events were bypassed using ionomycin and PMA, suggesting an additional and more distal mechanism for decreased transcription. In contrast, CD154 mRNA stability was similar in neonatal and adult cells after either ionomycin and PMA stimulation or engagement of the alphabeta TCR-CD3 complex. We conclude that decreased CD154 production by neonatal CD4(+) T cells is due to limitations in both proximal and distal activation events, which together ultimately limit CD154 gene transcription.

A T-cell-specific CD154 transcriptional enhancer located just upstream of the promoter

“…This is, in part, because the vast majority of CD4 T cells express CD154 following polyclonal activation ex vivo. 16 In addition, both Th1-and Th2-cloned CD4 T cell lines have been shown to express CD154 following activation. 17 However, long-term cloned T cell lines do not always represent the reality of primary CD4 T cells.…”

Altered mitochondrial response to activation of T-cells in neonate

“…-response, neonatal T-cells present other functional characteristics distinct from T-cells of the adult (11,23). Now we measured reduced baseline cytoplasmic Ca 2+ levels and reduced Ca Indeed we measured lower mitochondrial mass in neonatal CD4-cells than in those from the adult.…”

CD40, autophagy and Toxoplasma gondii

“…CD40-induced autophagic killing of T. gondii may be an important contributor to control of T. gondii in humans because CD40 induces killing of T. gondii independently of IFN-γ, STAT1, NOS2 and IRG (Andrade et al 2005a, Subauste et al 2007a. Defects in the CD40 pathway are likely relevant to at least three groups of patients that develop cerebral and/or ocular toxoplasmosis: patients with X-linked Hyper IgM syndrome who lack functional CD154 (Subauste et al 1999), newborns since neonatal CD4 + T cells exhibit impaired expression of CD154 (Durandy et al 1995, Nonoyama et al 1995, Julien et al 2003, Han et al 2004, Kaur et al 2007) and neonatal dendritic cells have reduced levels of CD40 (Kaur et al 2007). Impaired CD154 induction is particularly more pronounced in preterm babies (Kaur et al 2007), a finding relevant to toxoplasmosis in newborns since this is an infection acquired prior to birth.…”