Nutritional Regulation of PKCζ: Omega-3 Fatty Acids Shape Neonatal T Cell Development 2255253

Abstract Introduction Infants born to mothers with a family history of allergy often display transiently low cord blood T cell (CBTC) protein kinase C ζ (PKCζ) levels, which are associated with an increased allergy risk. Our previous studies have shown that PKCζ is a key regulator of neonatal T cell development, promoting a Th1 cytokine bias. Maternal supplementation with ω-3 polyunsaturated fatty acids (PUFAs) during pregnancy enhanced neonatal PKCζ expression and protected against allergic sensitisation. The purpose of our investigation was to discover whether PKCζ is both a biomarker of allergy risk and a target for allergy prevention. Methods CBTC and a surrogate CBTC culture maturation model was used to examine the levels of PKCζ and cytokines produced, employing monoclonal antibodies and flow cytometry. The modulatory effects of ω-3 PUFAs was assessed by adding the fatty acids directly to the CBTC. Similarly, when examining the effects of PUFA metabolic products. The role of the fatty acid metabolism was examined by using inhibitors of the lipoxygenase and cyclooxygenase pathways. Results The data demonstrate that ω-3 PUFA treatment caused an increase in PKCζ expressed by the CBTC. Interestingly we found that while some PUFAs caused an increase, others not only failed to increase the PKCζ levels but induced a decrease in this expression. The increase in PKCζ in CBTC induced by ω-3 DHA was reflected in a transition of cells maturing away from a Th2 allergy-promoting cytokine propensity (i.e. Th1 cytokine profile predominance). Its metabolism through the lipoxygenase pathway was import for this effect and it was related to the generation of resolving-D1. Conclusion The findings identify PKCζ as a target in newborn T cell to prevent development towards a Th2-cytokine propensity and potentially allergic sensitisation. These expand the ‘hygiene hypothesis’ to a nutrient environment that regulates PKCζ expression. Funding Source Adelaide Scholarships International (ASI, 2016-2020), University of Adelaide; Invest for Success grant, Robinson Research Institute, The University of Adelaide. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)