Functions for novel IL-15-responsive macrophages in the uterus during pregnancy

PROJECT SUMMARY The overall goal of this five-year proposal for a Mentored Clinical Scientist Research Career Development Award is for me to develop into a productive, independent academic investigator in the field of reproductive immunology. I completed an MD and a PhD in the field of basic cellular immunology, and I now seek to apply my interest in dysregulated immunity to the public health threat of adverse fetal and maternal outcomes of pregnancy. I graduated from the American Board of Pediatrics Accelerated Research Pathway for Residency in General, and I completed my Fellowship in Neonatal-Perinatal Medicine at Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). I joined the faculty of CHOP and Penn as an Attending Physician and Instructor in the Division of Neonatology. My mentor for this award, Dr. Edward M. Behrens, is a physician- scientist with a longstanding track record of scientific innovation and providing exceptional training to mentees at all levels. As an internationally-recognized expert in innate immunity and inflammatory disorders, Dr. Behrens’s work complements my own, and we are thus poised for productivity. My scientific advisory committee includes scientists and physician-scientists with collective expertise in all aspects of the proposed work, from placental biology to next-generation sequencing. I am also extremely fortunate to have the unreserved support of CHOP and Penn, whose combined resources are unmatched. Scientifically, this proposal focuses on roles for novel macrophages that I discovered under the guidance of Dr. Behrens, called CD122+Macs, in normal and threatened pregnancy. Enriched in the uterus in mice and humans, CD122+Macs express high levels of CD122, the hallmark of responsiveness to interleukin-15 (IL-15). These novel Macs signal and function when exposed to IL-15, surprising because killer lymphocytes like natural killer (NK) cells, not Macs, are the classical targets of IL-15. Disrupted homeostasis of IL-15 is associated with numerous adverse outcomes of pregnancy, including preeclampsia and abnormal feto-placental growth but through unknown mechanisms. Based on prior literature and my preliminary data, my central hypothesis is: IL- 15 exerts its influence over outcomes of pregnancy not only by maintaining NK cells but also by modulating the inflammatory properties of novel CD122+Macs. The aims of this proposal will establish: 1) Mechanisms by which CD122+Macs respond biochemically and transcriptionally to IL-15 and 2) IL-15-dependent requirements for CD122+Macs in pregnancy in vivo. This proposal will close major gaps in knowledge regarding the mechanism by which IL-15 acts on a novel cellular target to ensure maternal and fetal health during pregnancy. In accordance with my career development objective to become a field leader in reproductive immunology, my scientific proposal complements my current proficiency in cellular immunologic methods with training in advanced reproductive biology and bioinformatic methods.