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Distinct functional programming in human fetal and adult monocytes


Immune development in utero and early in life represents a critical period in human health. Until this point, most studies have been conducted using model organisms which may or may not mirror the actual developmental events found in humans. In this dissertation we strove to elucidate and understand the inherent differences between the fetal immune system and the adult, with a particular emphasis on the myeloid compartment. We extended these studies to look at the response to cytokines in utero as well as the potential response to HIV in utero, as well as whether these fetal phenotypes persisted after birth in both the myeloid and lymphoid compartment.

To carry out these studies we developed in vitro flow cytometry assays to phenotypically characterize cell surface markers and the phosphorylation responses present in the JAK/STAT pathways. We also developed a high-throughput qPCR genetic signature to assess umbilical cord blood for fetal and adult transcripts. We have shown that human fetal and adult classical monocytes have distinct baseline transcriptional and signaling programs as well as that transcriptional and signaling differences in fetal monocytes underlie stronger responses to cytokine stimulation. Further, we have identified and validated a genetic signature to query umbilical cord blood for the presence of fetal-like classical monocyte and naïve T cells. And finally we have demonstrated that fetal classical monocytes may more strongly induce HIV restriction factors in response to IFNγ than adult and have a stronger canonical and non-canonical STAT response to IFNα/β. These studies shed light, for the first time, on many of the immune mechanisms at play both during normal development in utero as well as in the case of infection.

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