Cellular expression and regulation of interleukin-27 in the neonatal immune syste

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DESCRIPTION (provided by applicant): Microbial infections are a major cause of infant mortality worldwide as a result of impaired immune defenses in this population. We have found that human umbilical cord blood-derived macrophages express interleukin (IL) - 27 at an elevated level as compared with healthy adult macrophages. We have further determined that elevated IL-27 production by newborns is maintained through infancy in a mouse model. IL-27 is a heterodimeric cytokine of the IL-12 family that is produced primarily by antigen presenting cells and is immunosuppressive toward a variety of immune cell types. Thus, elevated IL-27 expression early in life may contribute to some of the deficiencies described with immune responses by this population. The nature of this proposal is to understand the complete repertoire of cell types that contribute to elevated IL-27 production in neonates and infants as well as to further understand the molecular mechanisms responsible for differential expression. In the first aim, we will evaluate the cellular phenotypes of cells that produce IL-27 with a particular focus toward myeloid-derived suppressor cells. These cells have potent ability to suppressive inflammation and adaptive immunity. The second aim tests the hypothesis that IL-27 is regulated by epigenetic mechanisms that contribute to differences in age-related expression. This will focus on DNA methylation and nucleosome remodeling through histone modification. We have proposed research that investigates the impact of IL-27 on neonatal immune responses. Approaches to reduce expression of IL-27 in newborns and infants may improve vaccination responses and reduce susceptibility to infectious agents.