: Prolonged Th2-imbalanced responses during infancy are central to the induction of allergy and asthma. Immune responses elicited in newborn mice also demonstrate persistent Th2 deviation beyond the neonatal period. The parallels in responses across species make murine newborns an excellent model for examining the generation and maintenance of Th2 function in early life. The neonatal Th2 bias is well established, yet the underlying mechanisms remain unknown. The overall goal of this project is to examine the regulation of the murine neonatal Th2 bias, using IL-4 as the signature Th2 cytokine. Early after activation, neonatal CD4+ cells produce abundant IL-4. In contrast, adult Th2 development requires driving cytokines and multiple cell divisions over several days. Preliminary data suggest that the murine IL-4 locus may be differentially methylated in adult and neonatal T cells.
Aim 1 will compare methylation density at IL-4 regulatory regions in adult and neonatal cells by methylation-specific PCR. Subsequent experiments will relate methylation density with levels of IL-4 expression.
Aim 2 will investigate whether discrepancies in transcriptional regulation underlie differences in IL-4 production by adult and neonatal T cells. Transcription factor levels will be quantitated by Western blot and their DNA binding activity will be assayed by EMSA. Protein/DNA arrays will screen for existing transcription factors that potentially regulate neonatal IL-4 expression.
| 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 |
| Rose, Shawn; Guevara, Patricia; Farach, Sandra et al. (2006) The key regulators of adult T helper cell responses, STAT6 and T-bet, are established in early life in mice. Eur J Immunol 36:1241-53 |
