ROLE OF TRANSCRIPTION FACTOR C-MAF IN THE HTLV-1 LATENT INFECTION

成人T细胞白血病（ATL）是一种预后不良的恶性肿瘤，在感染人类T淋巴细胞病毒1型（HTLV-1）后经过漫长的潜伏期后发展。白血病细胞被认为来源于CCR 4 + CD 4 + Th 2或调节性T细胞，尽管HTLV-1也可以感染CD 8 +T细胞。值得注意的是，HTLV-1感染的CD 8 + T细胞在体内不会变成白血病。我们发现，在筛选参与HTLV-1白血病发生的CD 4 + T细胞中，Th 2相关转录因子c-Maf可能起以下关键作用：（1）c-Maf在新鲜ATL细胞中的组成性表达;（2）c-Maf对HTLV-1 Tax依赖的LTR激活的抑制作用;和（3）CD 4+和CD 8 + T细胞中c-Maf表达的差异，即，CD 4 + T细胞在静息和活化条件下均表达c-Maf，而CD 8 + T细胞仅在静息条件下表达c-Maf。这意味着c-Maf通过抗原刺激的CD 4 + T细胞中的LTR抑制而不是抗原刺激的CD 8 + T细胞中的LTR抑制来降低病毒相关蛋白的表达，包括作为CTL的有效靶标的Tax。这导致HTLV-1特异性CTL有效地消耗HTLV-1感染的CD 8 + T细胞。Tax反式激活后，HTLV-1感染的细胞也表达CCR 4配体CCL 22，化学吸引未感染的CCR 4 + CD 4 + T细胞，并通过细胞间相互作用将病毒颗粒传递给这些细胞。我们发现c-Maf还抑制CCL 22启动子的激活，表明c-Maf表达通过抑制CCL 22表达减少病毒向CCR 4 + CD 4 + T细胞的传播。

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.