Neonatal protein kinase C zeta expression determines the neonatal T‐Cell cytokine phenotype and predicts the development and severity of infant allergic disease

Abstract

The findings suggest a potential role for the use of PKCζ levels in cord blood T cells as a presymptomatic test to predict allergy risk in children, particularly offspring of allergic mothers, and that the basis of this relationship is related to cytokine patterns in mature T cells.

The role of PKCζ in cord blood T-cell maturation towards Th1 cytokine profile and its epigenetic regulation by fish oil

“…PKCζ expression in neonatal T-cells was analysed by Western blot assay as described previously [22,28]. Briefly, proteins were separated by SDS/PAGE (12% gel) and transferred to nitrocellulose membrane (Bio-Rad Laboratories, Gladesville, NSW, Australia).…”

“…Human CB T-cells, including those which were deficient in PKCζ, were maturated as previously described using phytohaemagglutinin (PHA) and IL-2 [22,28]. Maturation was gauged by flow cytometry, measuring the expression of CD45RA and CD45RO using anti-CD45RA-APC, anti-CD45RO-PE, anti-CD3-FITC or isotype control mix (IgG2b-APC, IgG2a-PE and IgG1-FITC) antibodies (all BD Biosciences).…”

“…Of the PKC isozymes, PKC ζ (PKCζ), an atypical isozyme of PKC family, is important for regulating asymmetric T-cell division that determines the subsequent fate of the cells [26]. We have previously reported that expression of PKCζ by neonatal T-cells was relatively lower as compared with adults and its levels in cord blood (CB) T-cells predicted the development and severity of allergic disease, indicating the significance of CB PKCζ levels as a predictive marker of disease risk [27,28]. Furthermore, the level of T-cell PKCζ at birth was positively associated with the capacity for IFNγ and tumour necrosis factor α (TNFα) production by in vitro matured neonatal T-cells and was negatively associated with allergen-specific interleukin (IL)-13 (IL-13) production at 6 months of age [28] suggesting that PKCζ may be involved in driving age-related maturation of T-cell response pattern.…”

“…We have previously reported that expression of PKCζ by neonatal T-cells was relatively lower as compared with adults and its levels in cord blood (CB) T-cells predicted the development and severity of allergic disease, indicating the significance of CB PKCζ levels as a predictive marker of disease risk [27,28]. Furthermore, the level of T-cell PKCζ at birth was positively associated with the capacity for IFNγ and tumour necrosis factor α (TNFα) production by in vitro matured neonatal T-cells and was negatively associated with allergen-specific interleukin (IL)-13 (IL-13) production at 6 months of age [28] suggesting that PKCζ may be involved in driving age-related maturation of T-cell response pattern. Furthermore, our previous studies demonstrate that maternal fish oil (ω-3 fatty acids) supplementation causes both immunomodulation and allergy protection in the offspring [29] and alters PKCζ expression by CB T-cells [27], suggesting that the genomic region that encodes PKCζ is readily amenable to modulation by in utero nutritional exposures.…”

PRKCZmethylation is associated with sunlight exposure in a North American but not a Mediterranean population

“…Specifically, two in vitro studies conducted in cells from SLE patients demonstrated induction of hypomethylation in CD4+ lymphocytes by UVB, suggesting a possible epigenetic mechanism (Li et al, 2010; Wu et al, 2013). T-cell expression of the gene containing our top methylation finding, PRKCZ , has been prospectively linked to infant allergic disease, highlighting its relevance to immune phenotypes (D’Vaz et al, 2012). Taken together, these studies imbue our preliminary findings in CD4+ lymphocytes with biological plausibility and stress the importance of future replication studies conducted in the same cell type.…”