Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD
Impaired thymic expression of tissue-restricted antigens licenses the de novo generation of autoreactive CD4+ T cells in acute GVHD
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DOI：
10.1182/blood-2014-08-597245
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发表时间：
2015-04-23
期刊：
影响因子：
20.3
通讯作者：
Krenger, Werner
中科院分区：
文献类型：
--
作者：
Dertschnig, Simone;Hauri-Hohl, Mathias M.;Krenger, Werner
在小鼠急性移植物抗宿主病（aGVHD）期间，可在宿主胸腺中从头产生自身反应性T细胞，这意味着自身耐受诱导受损。作为一种可能的机制，我们以前曾报道，成熟的髓质胸腺上皮细胞（mTEC高）表达的自身免疫调节的供体T细胞同种异体免疫在aGVHD的目标。mTEC高细胞池大小的下降，从总胸腺异位TRA库中清除单个组织限制性外周自身抗原（TRA），削弱了中枢耐受诱导的平台。在这里，我们提供的证据表明，在一个转基因小鼠使用卵清蛋白（OVA）作为模型替代TRA的OVA特异性CD4（+）T细胞的从头生产在急性GVHD是受损的胸腺异位OVA表达的mTEC高细胞的直接后果。因此，我们的数据表明，髓质mTEC（高）隔室的功能妥协可能会在慢性GVHD过程中将同种免疫与自身免疫的发展联系起来。
During acute graft-versus-host disease (aGVHD) in mice, autoreactive T cells can be generated de novo in the host thymus implying an impairment in self-tolerance induction. As a possible mechanism, we have previously reported that mature medullary thymic epithelial cells (mTEC high) expressing the autoimmune regulator are targets of donor T-cell alloimmunity during aGVHD. A decline in mTEC high cell pool size, which purges individual tissue-restricted peripheral self-antigens (TRA) from the total thymic ectopic TRA repertoire, weakens the platform for central tolerance induction. Here we provide evidence in a transgenic mousesystem using ovalbumin (OVA) as a model surrogate TRA that the de novo production of OVA-specific CD4(+) T cells during acute GVHD is a direct consequence of impaired thymic ectopic OVA expression in mTEC high cells. Our data, therefore, indicate that a functional compromise of the medullary mTEC(high) compartment may link alloimmunity to the development of autoimmunity during chronic GVHD.