The role of PKCζ in cord blood T-cell maturation towards Th1 cytokine profile and its epigenetic regulation by fish oil.
While immunodeficiency of immaturity of the neonate has been considered important as the basis for unusual susceptibility to infection, it has also been recognized that the ability to progress from an immature Th2 cytokine predominance to a Th1 profile has relevance in determining whether children will develop allergy, providing an opportunity for epigenetic regulation through environmental pressures. However, this notion remains relatively unexplored. Here, we present evidence that there are two major control points to explain the immunodeficiency in cord blood (CB) T-cells, a deficiency in interleukin (IL)-12 (IL-12) producing and IL-10 overproducing accessory cells, leading to a decreased interferon γ (IFNγ) synthesis and the other, an intrinsic defect in T-cell protein kinase C (PKC) ζ (PKCζ) expression. An important finding was that human CB T-cells rendered deficient in PKCζ, by shRNA knockdown, develop into low tumour necrosis factor α (TNFα) and IFNγ but increased IL-13 producing cells. Interestingly, we found that the increase in PKCζ levels in CB T-cells caused by prenatal supplementation with fish oil correlated with modifications of histone acetylation at the PKCζ gene (PRKCZ) promoter. The data demonstrate that PKCζ expression regulates the maturation of neonatal T-cells into specific functional phenotypes and that environmental influences may work via PKCζ to regulate these phenotypes and disease susceptibility.
Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, Marburg, Germany.
Hani
H
Harb
Department of Immunopathology, SA Pathology, Women and Children's Hospital Campus, School of Medicine; Robinson Research Institute and School of Biological Science, University of Adelaide, Adelaide, South Australia, Australia.
James
J
Irvine
School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
Manori
M
Amarasekera
Department of Immunopathology, SA Pathology, Women and Children's Hospital Campus, School of Medicine; Robinson Research Institute and School of Biological Science, University of Adelaide, Adelaide, South Australia, Australia.
Charles S
CS
Hii
Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, Marburg, Germany.
Dörthe A
DA
Kesper
Department of Immunopathology, SA Pathology, Women and Children's Hospital Campus, School of Medicine; Robinson Research Institute and School of Biological Science, University of Adelaide, Adelaide, South Australia, Australia.
YueFang
Y
Ma
School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
Nina
N
D'Vaz
Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, Marburg, Germany.
Harald
H
Renz
Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, Marburg, Germany potaczek@staff.uni-marburg.de.|John Paul II Hospital, Krakow, Poland.
Daniel P
DP
Potaczek
School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
Susan L
SL
Prescott
Department of Immunopathology, SA Pathology, Women and Children's Hospital Campus, School of Medicine; Robinson Research Institute and School of Biological Science, University of Adelaide, Adelaide, South Australia, Australia.
Antonio
A
Ferrante
D000107:Acetylation; D000704:Analysis of Variance; D017074:Common Variable Immunodeficiency / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D019587:Dietary Supplements; D004198:Disease Susceptibility / Q000276:immunology*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005312:Fetal Blood / Q000276:immunology*; D005395:Fish Oils / Q000008:administration & dosage / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099221:Protein Kinase C zeta
D016207:Cytokines; D005395:Fish Oils; D006657:Histones; D007371:Interferon-gamma; D018793:Interleukin-13; D011493:Protein Kinase C; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000099221:Protein Kinase C zeta
PKCζ; accessory cells; cord blood T-cell maturation; epigenetics; fish oil; neonates