A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice.
A critical epithelial survival axis regulated by MCL-1 maintains thymic function in mice.
复制标题
DOI：
10.1182/blood-2017-03-771576
复制
发表时间：
2017-12-07
期刊：
影响因子：
20.3
通讯作者：
Gray DHD
中科院分区：
文献类型：
--
作者：
Jain R;Sheridan JM;Policheni A;Heinlein M;Gandolfo LC;Dewson G;Smyth GK;Sansom SN;Fu NY;Visvader JE;Holländer GA;Strasser A;Gray DHD
T细胞分化受与胸腺上皮细胞（TEC）的相互作用的控制，并且该过程中的缺陷破坏免疫功能和耐受性。为了揭示在免疫缺陷中恢复胸腺功能和适应性免疫的新策略，我们试图确定TEC中控制生死决定的分子机制。在基因表达谱的指导下，我们建立了特异性删除TEC中促生存基因的小鼠模型。我们发现，虽然BCL-2和BCL-XL被认为是TEC稳态，但MCL-1缺乏早在E15.5就影响TEC，导致早期胸腺萎缩和T细胞淋巴细胞减少，到2个月龄时胸腺组织几乎完全丧失。MCL-1不是TEC分化所必需的，但对于成熟的皮质和髓质TEC的存活以及胸腺结构的维持是持续需要的。TEC营养因子在器官培养中的筛选显示，表皮生长因子（EGF）通过MAPK/ERK激酶活性上调MCL-1，为TEC存活提供了分子机制。这一支配TEC存活和胸腺功能的信号传导轴代表了胸腺保护和再生策略的新目标。
T cell differentiation is governed by interactions with thymic epithelial cells (TECs) and defects in this process undermine immune function and tolerance. To uncover new strategies to restore thymic function and adaptive immunity in immunodeficiency, we sought to determine the molecular mechanisms that control life and death decisions in TEC. Guided by gene expression profiling, we created mouse models which specifically deleted pro-survival genes in TEC. We found that while BCL-2 and BCL-XL were dispensable for TEC homeostasis, MCL-1 deficiency impacted on TEC as early as E15.5, resulting in early thymic atrophy and T cell lymphopenia, with near complete loss of thymic tissue by 2 months of age. MCL-1 was not necessary for TEC differentiation but was continually required for the survival of mature cortical and medullary TEC, and the maintenance of thymic architecture. A screen of TEC trophic factors in organ cultures showed that epidermal growth factor (EGF) upregulated MCL-1 via MAPK/ERK kinase activity, providing a molecular mechanism for the support of TEC survival. This signalling axis governing TEC survival and thymic function represents a new target for strategies for thymic protection and regeneration.
登录
查看更多内容
影响因子：
3.7
作者：
de Jonge HJ;Fehrmann RS;de Bont ES;Hofstra RM;Gerbens F;Kamps WA;de Vries EG;van der Zee AG;te Meerman GJ;ter Elst A
通讯作者：
ter Elst A
DOI：
10.1126/science.1218004
发表时间：
2012-04-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Dudakov JA;Hanash AM;Jenq RR;Young LF;Ghosh A;Singer NV;West ML;Smith OM;Holland AM;Tsai JJ;Boyd RL;van den Brink MR
通讯作者：
van den Brink MR
DOI：
10.1084/jem.20070795
发表时间：
2007-10-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gray D;Abramson J;Benoist C;Mathis D
通讯作者：
Mathis D
DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caton ML;Smith-Raska MR;Reizis B
通讯作者：
Reizis B
影响因子：
4.8
作者：
Chandra, Abhishek;Lan, Shenghui;Qin, Ling
通讯作者：
Qin, Ling