CD4+ T Cells in Infant Immunity Public Deposited

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Last Modified
  • March 19, 2019
Creator
  • dela Pena, Myra Grace
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Age and immune maturation are interdependent and dynamic processes. The infant immune system undergoes many developmental changes after birth, and compared to adults, cellular and molecular differences have been observed in infant immune responses. This dissertation is focused on the functional features of CD4+ T helper cells, as these cells are critical players in adaptive immunity. In general, infants show a bias toward CD4+ T helper 2 (Th2) responses, whereas adults generate Th1 responses against infectious diseases caused by intracellular pathogens. The infant's Th2 bias is reflected in increased susceptibility to infectious pathogens, and higher morbidity and mortality rates. We hypothesized that reduced functionality of infant CD4+ T cells would be due to intrinsic differences in the CD4+ T cell signaling that alters responsiveness of these cells, and thereby influences maturation, function and the generation of protective immunity. Specifically, we sought to i) characterize the immune development of CD4+ T cells in infants, (ii) determine infant CD4+ T cell response to exogenous cytokine stimulations, and (iii) assess the effectiveness of infant immunity in the control of a viral infection. First, we used rhesus macaques raised as specific pathogen free (SPF) and conventional status (non-SPF) to characterize basic immunological changes in peripheral blood cell populations with age and how they are affected by chronic cytomegalovirus infection (RhCMV). Our findings indicated that some age-related changes in major blood cell populations from birth to adulthood were common to both SPF and non-SPF macaques. We also demonstrated that chronic RhCMV infection modulated immune development over the lifetime of the host, evident in a more inflammatory response of juvenile RhCMV-infected macaques compared to SPF-juveniles. Second, we investigated the functional capacity of the infant immune system to control viral replication. We found that infant rhesus macaques were rapidly infected with RhCMV via the oral route and shed virus more frequently in bodily fluids and in higher titers when compared to adult macaques. Lastly, we used cross sectional human blood samples to test the hypothesis that the propensity towards Th2 response in infants is due to altered cytokine-receptor mediated signaling in CD4+ T cells. Our data showed that CD4+ T cells from cord blood (CB) and older infants differed in Th1 and Th2-associated cytokine receptor expression from adults. We also found that cytokine-signaling factors (JAKs and STATs) were differentially phosphorylated after cytokine treatment. Lastly, in vitro stimulation through the TCR and exogenous addition of IFN-gamma revealed differences in JAK/STAT related gene expression and cytokine productions between CB and adult CD4+ T cells. Together, our findings imply that cytokine signaling is developmentally controlled because responsiveness to cytokines increased with age in infant CD4+ T cells. The assessment of important functional parameters in CD4+ T cell development, such as cytokine and TCR signaling, from birth to adulthood can reveal mechanistic insights into how and why cellular immunity changes with age. How lifelong infections and other perturbation affect these immunological processes will likely impact both disease outcome and the generation of immunity. Unraveling the molecular mechanisms involved in these processes may aid in pediatric vaccine designs and therapeutic interventions.
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  • In Copyright
Advisor
  • Fiscus, Susan
  • Damania, Blossom
  • Wan, Yisong
  • Maile, Robert
  • Abel, Kristina
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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Place of publication
  • Chapel Hill, NC
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  • This item is restricted from public view for 1 year after publication.
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