Immune responses in neonates are often poor. As a result, neonates succumb to infections and diseases which seldom affect adults. The deficient immunity of neonates is associated with poor Th1 function. Because Th1 function is centrally important in cellular immune responses, a clear understanding of the dysregulation of Th1 lineage cells in neonates must be achieved to devise strategies leading to the prevention and treatment of disease in early life. This proposal aims to identify the cellular and biochemical mechanisms governing poor Th1 function in neonates in situ.
Specific Aims 1 and 2 focus on the inability of neonates to develop mature Th1 memory responses.
Specific Aim 3 will concentrate on the failure of neonates to generate enhanced primary Th1 responses when antigen is delivered in adjuvant.
Specific Aim 1 will test the hypothesis that the inability to generate Th1 dominant memory is due to developmental immaturity in both neonatal T cells and non-T cells. This will be tested by physically separating the two compartments in chimeric mice in vivo: the capacity of neonatal T cells to develop mature Th1 memory in adoptive adult TCRbeta-deficient hosts will be assessed; conversely, the capacity of neonatal TCRbeta-deficient hosts to support mature Th1 memory development by adult T cells will be examined. The ability of neonatal T cells to develop mature Th1 memory when antigen is delivered to intact neonates by mature adult dendritic cells will also be investigated. Lastly, whether neonatal transgenic T cells bearing mature, adult-derived TCR are able to achieve mature Th1 memory in situ, in adoptively transferred normal neonates, will be tested.
Specific Aim 2 will test the hypothesis that poor Th1 memory results from the preferential survival of Th2 cells due to developmental immaturity in the endogenous cytokine milieu. The frequencies of antigen-specific Th1 vs Th2 cells in neonates and adults will be measured following primary and secondary immunization. The antigen-driven production of proinflammatory cytokines known to modulate T cell development, function, and survival will be compared in immunized neonates and adults. Lastly, the capacity of exogenously administered IL-2 and/or proinflammatory cytokines to influence Th1 memory development in neonates will be assessed.
Specific Aim 3 will test the hypothesis that the failure of neonates to respond to adjuvant with increased primary Th1 activity is due to limited function within the APC compartment. First, the contributions of the innate properties of the neonatal T cell and non-T cell compartments to poor responsiveness to adjuvant will be assessed: neonatal T cells will be transferred to adult TCRbeta-deficient hosts, and vice versa, and primary Th1 responses to antigen in adjuvant will be assessed. Second, the adjuvant-induced upregulation of two major Th1-promoting cytokines, IL-12 and IL- 18, will be compared in intact neonates and adults. Finally, the capacity of coadministered IL-12 and IL-18 to enhance adjuvant- induced primary Th1 function in neonates will be tested.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunobiology Study Section (IMB)
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Macchiarini, Francesca
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University of Miami School of Medicine
Schools of Medicine
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Yoshimoto, Momoko; Yoder, Mervin C; Guevara, Patricia et al. (2013) The murine Th2 locus undergoes epigenetic modification in the thymus during fetal and postnatal ontogeny. PLoS One 8:e51587
Adkins, Becky (2013) Neonatal immunology: responses to pathogenic microorganisms and epigenetics reveal an ""immunodiverse"" developmental state. Immunol Res 57:246-57
Adkins, Becky; Contractor, Nikhat (2011) Immune responses of female BALB/c and C57BL/6 neonatal mice to vaccination or intestinal infection are unaltered by exposure to breast milk lycopene. J Nutr 141:1326-30
Echeverry, Andrea; Saijo, Shinobu; Schesser, Kurt et al. (2010) Yersinia enterocolitica promotes robust mucosal inflammatory T-cell immunity in murine neonates. Infect Immun 78:3595-608
Opiela, Shannon J; Koru-Sengul, Tulay; Adkins, Becky (2009) Murine neonatal recent thymic emigrants are phenotypically and functionally distinct from adult recent thymic emigrants. Blood 113:5635-43
Zaghouani, Habib; Hoeman, Christine M; Adkins, Becky (2009) Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells. Trends Immunol 30:585-91
Opiela, Shannon J; Levy, Robert B; Adkins, Becky (2008) Murine neonates develop vigorous in vivo cytotoxic and Th1/Th2 responses upon exposure to low doses of NIMA-like alloantigens. Blood 112:1530-8
Adkins, Becky (2007) Heterogeneity in the CD4 T Cell Compartment and the Variability of Neonatal Immune Responsiveness. Curr Immunol Rev 3:151-159
Rose, Shawn; Lichtenheld, Mathias; Foote, Monica R et al. (2007) Murine neonatal CD4+ cells are poised for rapid Th2 effector-like function. J Immunol 178:2667-78
Echeverry, Andrea; Schesser, Kurt; Adkins, Becky (2007) Murine neonates are highly resistant to Yersinia enterocolitica following orogastric exposure. Infect Immun 75:2234-43

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