Infants born prematurely (preterm, PT) are highly susceptible to viral infections, raising questions regarding their CD8+ T cell function. Cord blood CD8+ T cells from PT infants are more highly activated and are hyper- responsive to inflammatory stimuli in vitro. The objective of this proposal is to investigate abnormalities in th cytokine milieu associated with in utero infection, cytokine signal transduction in umbilical cord CD8+ T cells and downstream effects on CD8+ T cell function and repertoire in PT infants. We hypothesize that inflammatory mediators present in clinical chorioamnionitis disrupt normal fetal T cell homeostasis, resulting in expansion of CD8+ T cells that are functionally dysregulated and less diverse. This finding would have two important consequences on the preterm host immune system: 1) The immune system becomes dominated by CD8+ T cells that are hyper-responsive and potentiate inflammation, and 2) Compromised CD8+ T cell receptor repertoire that leaves them less able to mount protective immune responses to pathogen. The immediate goal of our project is to characterize the interaction between extrinsic environmental factors and intrinsic developmentally regulated mechanisms of CD8+ T cell activation. My long-term goal is to exploit these mechanisms pharmacologically to enhance or attenuate CD8+ T cell responses in PT infants, thereby improving their outcomes. To achieve our goals, we will interrogate cytokine pathways associated with CD8+ T cell activation and differentiation. We will characterize, by V? CDR3 mRNA sequencing, the CD8+ TCR repertoire diversity in PT infant cord blood and the degree to which it is compromised by in utero infections. We will identify from within an existing longitudinal study cohort a set of subjects born d 32 weeks gestation, and full term controls, with and without infection. Comparisons of CD8+ T cell phenotype, cytokine signal transduction, plasma cytokine concentrations and TCR diversity index will be made between cases and controls to reveal the relative contributions of development and environmental changes on CD8+ T cell development. The overall K08 application is designed to build a foundation of technical, intellectual and leadership skills required to transition into independence. The career development plan includes didactics to strengthen my knowledge base in T cell biology and fetal development, grant writing and immune modeling. I have selected scientific and career development seminars that I will attend regularly, and national meetings in order to identify novel research directions and increase recognition of my work in the larger field of neonatal immunology. My experienced mentors and advisory committee will monitor adherence to the detailed three- year productivity and developmental progress timeline. Invested mentorship, support for conducting translational science, depth of T cell immunology expertise and equipment, and a collaborative environment at the University of Rochester will provide the necessary tools with which I can build my early career.
Infants born extremely premature suffer from high rates of infection and diseases caused by excessive inflammation. Because we know little about how immune cell behavior is altered by sudden exposure to infectious and environmental insults at a time when organs are still developing, there are few safe medications available to treat their unique diseases caused by inflammation. We have evidence that CD8+ T cells, immune cells responsible for killing infected targets, are easily turned on by an inflammatory environment in premature infants, increasing the risk for CD8+ T cells to inappropriately attack fragile, developing organs. This project seeks to understand mechanisms underlying CD8+ T cell activation, in order to eventually develop medications to selectively enhance or dampen CD8+ T cell activity, thereby improving outcomes for these vulnerable patients.
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