T helper responses in early life in the mouse and, notably, allergen-specific responses in human infants are biased to Th2 function. This early life Th2 dominance is associated with the development of Th2- mediated diseases, such as allergy and asthma. With Th2-mediated diseases on the rise, there is a clear need for the development of new approaches to prevent and treat pathological Th2 activity. However, what is currently lacking is a thorough understanding of the basis of early life Th2 function. This information is critical for formulating effective strategies to target Th2-mediated pediatric disease. To this end, the long term goals of this proposal are to determine the molecular and cellular regulation of neonatal Th2 responses.
Specific Aim 1 will focus on the molecular events governing neonatal Th2 function. We have generated compelling evidence that the neonatal Th2 bias is regulated, at least in part, at the epigenetic level. Naive neonatal CD4+ cells, unlike adult CD4+cells, show demethylation of a key regulatory region in the Th2 locus. Thus, we will further investigate this phenomenon, its specificity and its developmental origin, and test the idea that DMA methylation is critical for defining developmental differences in Th2 effector differentiation and function.
Specific Aims 2 and 3 will examine cellular components enriched in neonates that are strong candidates for being the major sources of Th2 activity. First, since many neonatal CD4+ cells are likely to be direct descendants of fetal precursors, Specific Aim 2 will test the idea that neonatal Th2 cells are of fetal origin. Support for this hypothesis comes from our observation that peripheral CD4+ cells derived from fetal thymocytes have enhanced Th2 function. Second, the peripheral CD4+ population in neonates contains proportionally many more recent thymic emigrants (RTE) than found in peripheral populations in adults. Therefore, Specific Aim 3 will address the hypothesis that RTE are the source of Th2 function in neonates. This idea is supported by our findings that the function of peripheral CD4+ cells in neonates resembles that of RTE in adults. ? ?
|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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