Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways.
Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways.
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DOI：
10.4049/jimmunol.1302550
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发表时间：
2014-01-15
期刊：
影响因子：
--
通讯作者：
Hodes RJ
中科院分区：
文献类型：
--
作者：
Williams JA;Zhang J;Jeon H;Nitta T;Ohigashi I;Klug D;Kruhlak MJ;Choudhury B;Sharrow SO;Granger L;Adams A;Eckhaus MA;Jenkinson SR;Richie ER;Gress RE;Takahama Y;Hodes RJ
T细胞库在胸腺发育过程中的一个关键过程是诱导自身耐受性。发育中的T细胞的耐受性高度依赖于胸腺上皮细胞(MTEC)，而mTEC的发育又需要成熟的单个阳性(SP)胸腺细胞发出信号，这种双向关系被称为胸腺串扰。我们发现，CD28CD80/86和CD40CD40L共刺激相互作用，介导了负选择和自我耐受，上调了胸腺LTα、LTβ和RANK的表达，是骨髓发育所必需的。CD28-CD80/86和CD40-CD40L的联合缺失导致mTEC发育的严重缺陷，与没有SP胸腺细胞的情况下观察到的情况类似。即使在高亲和力TCR-配体相互作用的TCR转基因模型中，也保持了对共刺激信号的这一要求。CD40/CD80/86 KO小鼠胸腺上皮细胞在改变的胸腺上皮环境中成熟，在体外具有高度的自身反应性，在体内同种过继移植中具有致死性，表明这些共刺激途径在自身耐受和胸腺上皮发育中起着关键作用。这些发现表明，CD28-CD80/86和CD40-CD40L通路之间的协同作用是正常的髓质上皮和维持胸腺细胞发育中的自我耐受所必需的。
A critical process during thymic development of the T cell repertoire is the induction of self-tolerance. Tolerance in developing T cells is highly dependent on medullary thymic epithelial cells (mTEC) and mTEC development in turn requires signals from mature single positive (SP) thymocytes, a bidirectional relationship termed thymus crosstalk. We show that CD28-CD80/86 and CD40-CD40L costimulatory interactions, which mediate negative selection and self-tolerance, upregulate expression of LTα, LTβ and RANK in the thymus and are necessary for medullary development. Combined absence of CD28-CD80/86 and CD40-CD40L results in profound deficiency in mTEC development comparable to that observed in the absence of SP thymocytes. This requirement for costimulatory signaling is maintained even in a TCR transgenic model of high affinity TCR-ligand interactions. CD4 thymocytes maturing in the altered thymic epithelial environment of CD40/CD80/86 KO mice are highly autoreactive in vitro and are lethal in congenic adoptive transfer in vivo, demonstrating a critical role for these costimulatory pathways in self-tolerance as well as thymic epithelial development. These findings demonstrate that cooperativity between CD28-CD80/86 and CD40-CD40L pathways is required for normal medullary epithelium and for maintenance of self-tolerance in thymocyte development.
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