| Budget Amount *help |
¥3,790,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
Adult T-cell leukemia (ATL) is a malignancy with poor prognosis, which develops after a lengthy latent period of infection with human T-lymphotropic virus type 1 (HTLV-1). Leukemic cells are thought to be derived from CCR4+CD4+Th2 or regulatory T cells, although HTLV-1 can also infect CD8+T cells. Notably, HTLV-1-infected CD8+ T cells- do not become leukemic in vivo. The key is to identify the difference between HTLV-1-infected CD4+ and HTLV-1-infected CD8+T cells.
We noticed that a Th2-related transcription factor c-Maf might play the following key roles in selecting the CD4+ T cells involved in HTLV-1 leukemogenesis: (1) constitutive expression of c-Maf in fresh ATL cells; (2) inhibitory effect of c-Maf on HTLV-1 Tax-dependent LTR activation; and (3) difference in c-Maf expression in CD4+ and CD8+ T cells, i.e., CD4+ T cells express c-Maf under both resting and activating conditions, while CD8+ T cells express c-Maf only under resting conditions. This implies that c-Maf reduces the expression of virus-related proteins, including Tax that is a potent target of CTLs, via LTR suppression in antigen-stimulated CD4+ T cells but not antigen-stimulated CD8+ T cells. This results in the effective depletion of HTLV-1-infected CD8+ T cells by HTLV-1-specific CTLs.
Following Tax transactivation, HTLV-1-infected cells also express the CCR4 ligand CCL22, chemoattract uninfected CCR4+CD4+ T cells, and transmit viral particles to these cells via cell-to-cell interactions. We found that c-Maf also suppresses the activation of the CCL22 promoter, suggesting that c-Maf expression decreases viral transmission to CCR4+CD4+ T cells by suppressing CCL22 expression.
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