Epithelial LTβR signaling controls the population size of the progenitors of medullary thymic epithelial cells in neonatal mice.
Epithelial LTβR signaling controls the population size of the progenitors of medullary thymic epithelial cells in neonatal mice.
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上皮 LTβR 信号控制新生小鼠髓质胸腺上皮细胞祖细胞的群体大小
DOI：
10.1038/srep44481
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发表时间：
2017-03-14
影响因子：
4.6
通讯作者：
Zhu M
中科院分区：
文献类型：
--
作者：
Wu W;Shi Y;Xia H;Chai Q;Jin C;Ren B;Zhu M
T细胞中枢耐受的建立关键依赖于胸腺髓质上皮细胞（mTECs）的发育和维持。光毒素β受体（LTβR）信号传导的中断导致mTEC数量急剧减少。然而，LTβR是否直接或间接控制mTECs仍不确定; LTβR如何控制这一过程也仍不清楚。本研究利用K14-Cre × Ltbrfl/fl条件性基因敲除（cKO）小鼠，证明了上皮细胞内源性LTβR对mTEC的生后发育至关重要。从机制上讲，LTβR并不直接影响mTEC的增殖或存活;在不存在LTβR的情况下，mTEC从MHC-IIlo阶段成熟到MHC-IIhi阶段也没有改变;有趣的是，在新生儿阶段发现LTβR cKO小鼠中mTEC祖细胞（Cld 3，4 hiSSEA-1+）的数量显著减少，但在E18.5时则没有。因此，上皮细胞LTβR缺陷导致胸腺阴性选择的显著缺陷，如OT-I和RIP-OVA转基因小鼠系统所证实的。总之，我们的研究阐明了LTβR对mTEC发育和功能的上皮内在作用;更重要的是，它揭示了LTβR在控制mTEC祖细胞群体大小方面的先前未被认识的功能。
The establishment of T cell central tolerance critically relies on the development and maintenance of the medullary thymic epithelial cells (mTECs). Disrupted signaling of lymphotoxin beta receptor (LTβR) results in dramatically reduced mTEC population. However, whether LTβR directly or indirectly control mTECs remains undetermined; how LTβR controls this process also remain unclear. In this study, by utilizing K14-Cre × Ltbrfl/fl conditional knockout (cKO) mice, we show that epithelial intrinsic LTβR was essential for the mTEC development postnatally. Mechanistically, LTβR did not directly impact the proliferation or survival of mTECs; the maturation of mTECs from MHC-IIlo to MHC-IIhi stage was also unaltered in the absence of LTβR; interestingly, the number of mTEC progenitors (Cld3,4hiSSEA-1+) was found significantly reduced in LTβR cKO mice at the neonatal stage, but not at E18.5. Consequently, epithelial deficiency of LTβR resulted in significant defect of thymic negative selection as demonstrated using OT-I and RIP-OVA transgenic mouse system. In summary, our study clarifies the epithelial intrinsic role of LTβR on mTEC development and function; more importantly, it reveals a previously unrecognized function of LTβR on the control of the size of mTEC progenitor population.