Epigenetic patterns at the neonatal Th2 cytokine locus are developmentally regulated (85.2)

Abstract

Abstract Murine neonatal immune responses are commonly Th2 biased, characterized by rapid and high level Th2 cytokine production. These Th2-biased responses entail cell-intrinsic properties whose molecular basis is now beginning to become unveiled. We have recently found that the Th2 regulatory region CNS-1 is nearly 25% more demethylated in naïve neonatal CD4+ lymph node T cells and in CD4+ single positive (SP) thymocytes than in the same adult populations. Importantly, IL-4-expressing neonatal thymocytes exhibit substantially greater levels of hypomethylation at CNS-1 compared to unactivated cells. These results suggest that a hypomethylated state at CNS-1 is permissive for IL-4 expression in neonatal cells. Additional studies have revealed that CNS-1 exists in this highly demethylated state in freshly isolated fetal (d15 gestation) thymocytes, which are predominantly double negative cells and are the precursors of CD4+ SP thymocytes found in the neonate. These new findings suggest that epigenetic patterns at the neonatal Th2 cytokine locus are established within the fetal thymus, or even earlier, possibly in fetal liver precursor cells. Together, these observations lead to the intriguing idea that epigenetic modifications may be used as a developmental strategy within the CD4+ T helper cell lineage to achieve differential expression of cytokine genes at different times of life. This work was supported by NIAID grant number R01 AI44923-02 (B.A.).