PKCζ activation promotes maturation of cord blood T cells towards a Th1 IFN-γ propensity.

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dc.contributor.authorPerveen, K.
dc.contributor.authorQuach, A.
dc.contributor.authorStark, M.J.
dc.contributor.authorPrescott, S.
dc.contributor.authorBarry, S.C.
dc.contributor.authorHii, C.S.
dc.contributor.authorFerrante, A.
dc.date.issued2023
dc.description.abstractA significant number of babies present transiently with low protein kinase C zeta (PKCζ) levels in cord blood T cells (CBTC), associated with reduced ability to transition from a neonatal Th2 to a mature Th1 cytokine bias, leading to a higher risk of developing allergic sensitisation, compared to neonates whose T cells have 'normal' PKCζ levels. However, the importance of PKCζ signalling in regulating their differentiation from a Th2 to a Th1 cytokine phenotype propensity remains undefined. To define the role of PKCζ signalling in the regulation of CBTC differentiation from a Th2 to a Th1cytokine phenotype we have developed a neonatal T cell maturation model which enables the cells to develop to CD45RA- /CD45RO+ T cells while maintaining the Th2 immature cytokine bias, despite having normal levels of PKCζ. The immature cells were treated with phytohaemagglutinin, but in addition with phorbol 12-myristate 13-acetate (PMA), an agonist which does not activate PKCζ. This was compared to development in CBTC in which the cells were transfected to express constitutively active PKCζ. The lack of PKCζ activation by PMA was monitored by western blot for phospho-PKCζ and translocation from cell cytosol to the membrane by confocal microscopy. The findings demonstrate that PMA fails to activate PKCζ in CBTC. The data show that CBTC matured under the influence of the PKC stimulator, PMA, maintain a Th2 cytokine bias, characterised by robust IL-4 and minimal interferon gamma production (IFN-γ), and lack of expression of transcriptional factor, T-bet. This was also reflected in the production of a range of other Th2/Th1 cytokines. Interestingly, introduction of a constitutively active PKCζ mutant into CBTC promoted development towards a Th1 profile with high IFN-γ production. The findings demonstrate that PKCζ signalling is essential for the immature neonatal T cells to transition from a Th2 to a Th1 cytokine production bias.
dc.description.statementofresponsibilityKhalida Perveen, Alex Quach, Michael J. Stark, Susan Prescott, Simon C. Barry, Charles S. Hii, Antonio Ferrante
dc.identifier.citationImmunology, 2023; 170(3):359-373
dc.identifier.doi10.1111/imm.13674
dc.identifier.issn0019-2805
dc.identifier.issn1365-2567
dc.identifier.orcidPerveen, K. [0000-0002-1499-1736]
dc.identifier.orcidQuach, A. [0000-0003-1912-7581]
dc.identifier.orcidStark, M.J. [0000-0001-5518-1580] [0000-0003-1835-8679]
dc.identifier.orcidBarry, S.C. [0000-0002-0597-7609]
dc.identifier.orcidHii, C.S. [0000-0002-7107-8935]
dc.identifier.orcidFerrante, A. [0000-0002-2581-6407]
dc.identifier.urihttps://hdl.handle.net/2440/138824
dc.language.isoen
dc.publisherWiley
dc.relation.grantNHMRC
dc.rights© 2023 The Authors. Immunology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.source.urihttps://doi.org/10.1111/imm.13674
dc.subjectCD4+ and CD8+ T cells
dc.subjectPKC isozymes
dc.subjectPKCζ
dc.subjectT cell maturation
dc.subjectTh1 and Th2 subsets
dc.subjectallergy
dc.subjectcord blood T cells
dc.subjectcytokines
dc.subjectneonate
dc.titlePKCζ activation promotes maturation of cord blood T cells towards a Th1 IFN-γ propensity.
dc.title.alternativePKCZ activation promotes maturation of cord blood T cells towards a Th1 IFN-G propensity.
dc.typeJournal article
pubs.publication-statusPublished

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