Inflammatory disease and lymphomagenesis caused by deletion of the Myc antagonist Mnt in T cells
Inflammatory disease and lymphomagenesis caused by deletion of the Myc antagonist Mnt in T cells
复制标题
DOI：
10.1128/mcb.26.6.2080-2092.2006
复制
发表时间：
2006-03-01
影响因子：
5.3
通讯作者：
Hurlin, PJ
中科院分区：
文献类型：
--
作者：
Dezfouli, S;Bakke, A;Hurlin, PJ
Mnt是一种Max相互作用蛋白，可拮抗培养细胞中Myc癌蛋白的活性。Mnt基因敲除小鼠出生后很快死亡，但乳腺上皮中Mnt的条件性缺失导致肿瘤形成。这些和相关的数据表明，Mnt功能作为一种肿瘤抑制剂。在这里，我们表明T细胞中Mnt的条件性缺失导致肿瘤形成，但也导致炎症性疾病。Mnt的缺失导致胸腺T细胞凋亡增加，并干扰T细胞发育，但导致脾、肝和淋巴结肿大。脾脏和淋巴结中T细胞的比例降低，非T细胞免疫细胞群中的细胞数量升高。免疫稳态的破坏与T辅助细胞1（Th 1）细胞因子的产生和活化的Mnt-缺陷型CD 4（+）T细胞的增殖增强有关。与体内Th 1极化一致，出现了广泛的肠道炎症和肝坏死。最后，大多数T细胞中缺乏Mnt的小鼠最终死于T细胞淋巴瘤。这些结果加强了Mnt作为肿瘤抑制因子发挥作用的论点，并揭示了Mnt在调节T细胞发育和T细胞依赖性免疫稳态中的关键和令人惊讶的作用。
Mnt is a Max-interacting protein that can antagonize the activities of Myc oncoproteins in cultured cells. Mnt null mice die soon after birth, but conditional deletion of Mnt in breast epithelium leads to tumor formation. These and related data suggest that Mnt functions as a tumor suppressor. Here we show that conditional deletion of Mnt in T cells leads to tumor formation but also causes inflammatory disease. Deletion of Mnt caused increased apoptosis of thymic T cells and interfered with T-cell development yet led to spleen, liver, and lymph node enlargement. The proportion of T cells in the spleen and lymph nodes was reduced, and the numbers of cells in non-T-cell immune cell populations were elevated. The disruption of immune homeostasis is linked to a strong skewing toward production of T-helper 1 (Th1) cytokines and enhanced proliferation of activated Mnt-deticient CD4(+) T cells. Consistent with Th1 polarization in vivo, extensive intestinal inflammation and liver necrosis developed. Finally, most mice lacking Mnt in T cells ultimately succumbed to T-cell lymphoma. These results strengthen the argument that Mnt functions as a tumor suppressor and reveal a critical and surprising role for Mnt in the regulation of T-cell development and in T-cell-dependent immune homeostasis.