Development of therapeutic strategy for allergic diseases based on the genome information

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From our previous study, the expression of IL-4 gene is found to be epigenetically regulated in CD4^+ T cells. However, these gene regulation mechanisms are virtually unclear. Therefore, we investigated the role of an evolutionarily conserved 〜200bp non-coding sequence in the intergenic region between IL-4 and KIF3 genes using GFP reporter transgenic (Tg) mice. Notch signals have been shown to affect the cellular differentiation of tissue throughout the life of multicellular organisms. RBP-Jκ is a downstream common transcriptional mediator in Notch signaling. The T cell specific deficiency of RBP-J□ resulted in selective loss of Th2 development. Distal 3' enhancer in Il4 locus that correlates with the conserved regions called, Conserved non-coding sequences (CNS)-2, contained multiple possible binding sites for RBP-Jκ. Using a transgenic GFP reporter system, we showed that binding of RBP-Jκ to the CNS-2 enhancer regulated initial IL-4 production from NKT cells and a subset of CD44^<hi> memory phenotype (MP) CD4 T cells. The Rbp-j deficient T cells exhibited marked reduction of both CNS-2 enhancer activity and initial IL-4 from NKT and MP CD4 T cells. Depletion of CNS-2 active CD4 T cells markedly decreased Th2 differentiation from naive CD4 T cells. These results indicate the functional importance of Notch signal and MP CD4 T cells in facilitating Th2 differentiation of naive CD4 T cells during initial stage of antigen induced allergic responses.