Understanding Molecular Pathways for Fetal T Cell Development and Function

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 DESCRIPTION (provided by applicant): The fetal immune system carries out the crucial task of establishing immune tolerance to self and to maternal antigen, thus avoiding autoimmunity and preventing anti-maternal responses that might otherwise terminate a pregnancy. These responses, while adaptive in utero, likely contribute to the immune dysfunction observed in premature newborns that make them highly susceptible to infection. By the time of normal full-term birth, the developing immune system must prepare to encounter both commensal and pathogenic organisms. This requires acquisition of adult-like responses capable of generating sterilizing immunity. The mechanisms governing this programmatic switching in utero are currently unknown. We have, however, identified candidate genes that may govern immune program maturation. The zinc finger transcription factors, Kruppel-like factor (KLF) 10, and KLF9, are highly and specifically expressed in fetal and adult T cells, respectively. Both of these proteins induce the modulation of target gene expression through recruitment of cofactors that deposit repressive or permissive histone marks. Stimulation of naive CD4+ T cells in the presence of TGFß typically causes them to differentiate into regulatory T cells (Tregs). This process is now know to require KLF10-dependent histone acetylation at key regulatory sites in the FoxP3 locus. We hypothesize that KLF10 activates the FoxP3 locus in fetal T cells by inducing permissive histone modifications, which facilitates the differentiation of naïve fetal T cells into tolerogenic Tregs. We also hypothesize that KLF9 expression results in silencing of FoxP3 in order to allow for the development of sterilizing T cell immunity. This hypothesis will be addressed in the experiments of the following specific aims: (1) to determine whether KLF10 and KLF9 facilitate the expression of signature fetal or adult genes through histone modification and (2) to determine whether KLF10 drives the differentiation of fetal naïve T cells into Tregs by maintaining an inducible chromatin state at the FoxP3 locus. Findings from this study will provide a deeper understanding of normal immune ontogeny in utero, and therefore, could help guide strategies for the modulation of the neonatal immune response and prevention of the complications of prematurity.