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Nat Immunol:蛋白酶体介导CD8 T细胞胸腺选择过程

2016-07-18 佚名 生物谷

在T细胞发育过程,不成熟的胸腺细胞通过TCR基因的重排产生多种不同的受体储藏库。之后,免疫系统通过阳性选择过程挑选有用的受体类型,并通过阴性选择的过程将有害的自体免疫性受体排除出最终的受体库中。对于每个T细胞来说,这些关键的检查点的通过依赖于TCR接受到的信号,即来自于MHC-自体抗原多肽复合体的刺激。大部分有MHC-I呈递的自体抗原主要蛋白酶体降解胞内蛋白产生。蛋白媒体包含六个活性位点,由三个不

在T细胞发育过程,不成熟的胸腺细胞通过TCR基因的重排产生多种不同的受体储藏库。之后,免疫系统通过阳性选择过程挑选有用的受体类型,并通过阴性选择的过程将有害的自体免疫性受体排除出最终的受体库中。对于每个T细胞来说,这些关键的检查点的通过依赖于TCR接受到的信号,即来自于MHC-自体抗原多肽复合体的刺激。

大部分有MHC-I呈递的自体抗原主要蛋白酶体降解胞内蛋白产生。蛋白媒体包含六个活性位点,由三个不同的B-亚基组成:B1/B2/B3各两个。根据各亚基 种类的不同,蛋白酶体还可以再分为胸腺蛋白酶体((β1i, β2i and β5t)、组成性蛋白酶体(β1c, β2c and β5c)、免疫性蛋白酶体(β1i, β2i and β5i)以及混合型蛋白酶体(不同c与i亚基的组合)。由于不同亚基的活性位点以及催化特征都不太一致,因此能够产生多种不同的抗原多肽。由于胸腺蛋白酶体主要表达于胸腺基质上皮细胞(cTEC)中,因此由cTEC产生的用于阳性选择的多肽与机体其它部位产生的多肽类型(比如mTEC以及用于介导阴性选择的胸腺树突状细胞)应该存在差异。

研究表明,缺失胸腺蛋白酶体b5t亚基的小鼠存在一定的CD8 T细胞成熟障碍。这表明阳性选择可能需要特异性的抗原表位驱动。一种看法认为,B5t的缺失导致了用于驱动阳性选择的特异性多肽的生成障碍,从而导致成熟的CD8 T细胞的减少,另一种看法则认为,胸腺蛋白酶体催化产生的抗原多肽不会出现在阴性选择过程中,因此与上述多肽有特异性结合的T细胞更加容易通过阴性选择进而成熟。而B5t的缺失导致了这类T细胞的数量的降低。总之,上述两种看法均存在,但无法证明哪一种的正确的,哪一种是错误的。

为了了解T细胞发育过程中特异性的蛋白酶体亚基的作用,来自麻省大学医学院的Kenneth L Rock课题组进行了深入研究,相关结果发表在最近一期的《Nature Immunology》杂志上。

首先,作者构建了缺乏蛋白酶体亚基β1i, β2i, β5i 以及β5t的突变体小鼠(4个基因均缺失)。这类小鼠体内仅仅有组成性的蛋白酶体的表达。突变体小鼠能够正常生长,胸腺大小与野生型小鼠没有差异,而且具有与野生型小鼠相当数量的双阴性(CD4- CD8-)T细胞以及双阳性(CD4+ CD8+)T细胞。相反地,这类小鼠体内成熟的CD8单阳性细胞存在明显降低(下降90%),而成熟的CD4 T细胞则没有明显下降。为了研究这一缺陷的产生是否与胸腺基质细胞有关。作者构建了骨髓重建小鼠,即将野生小鼠的骨髓细胞转入辐照后的突变体小鼠体内,此时重构小鼠的骨髓来源的细胞均为野生型,而包括胸腺基质细胞在内的体细胞则为突变体基因型。结果显示,这部分小鼠体内成熟的CD8 T细胞数量相比对照组仍有明显的下降,这一结果表明胸腺基质细胞在CD8 T细胞胸腺选择成熟过程中具有重要的作用。

之后,作者研究了蛋白酶体的缺失如何影响了CD8 T细胞的阳性选择。他们利用骨髓重建的方法将OT-1转基因小鼠的骨髓打入野生型或突变体小鼠体内。结果显示,突变体的胸腺中产生的成熟的CD8单阳性T细胞数量明显低于对照组,CD4单阳性的OT-I胸腺细胞数量也有明显下降。另外,在突变体小鼠中,存活的CD4单阳性胸腺细胞TCR的表达量相比野生型也明显较低。由于CD4单阳性表明这部分胸腺细胞已经经过了阳性选择,因此这一结果表明:在缺失了特异性蛋白酶体的情况下,OT-1的阳性选择存在缺陷。接下来,作者利用多克隆的T细胞证明了上述的试验结果。

在阳性选择之后,CD69阳性的胸腺细胞能够上调CCR7的表达量,从而帮助其迁移到胸腺的髓质区域。作者发现,野生型与突变体小鼠其CCR7intCD69+CD103+胸腺细胞的数量相当,这说明CD8 T细胞并没有在这一检查点受到阻碍。即CD8T细胞能够在突变体的胸腺环境中顺利完成阳性选择,并表达髓质归巢趋化因子受体帮助其完成系别决定过程(lineage commitment)

进一步,作者证明胸腺特异性蛋白酶体的缺失影响的关键过程是胸腺细胞经历阳性选择后到达阴性选择的这一步。即,在缺失突变体的环境中,小鼠体内的CD8 T细胞能够顺利完成阳性选择,但不能顺利经过阴性选择成为成熟的单阳性T细胞。

原始出处

Eleanor Z Kincaid, Shigeo Murata, Keiji Tanaka & Kenneth L Rock.Specialized proteasome subunits have an essential role in the thymic selection of CD8+ T cells.Nat Immunol.2016

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