Hôpital La Pitié-Salpêtrière, UPMC Univ Paris 06, UMR 7211, Paris, France.
Eur J Immunol. 2012 Mar;42(3):760-70. doi: 10.1002/eji.201141798. Epub 2011 Dec 20.
In humanized mice, the T-cell repertoire is derived from genetically identical human progenitors in distinct animals. Thus, careful comparison of the T-cell repertoires of humanized mice with those of humans may reveal the contribution of genetic determinism on T-cell repertoire formation. Here, we performed a comprehensive assessment of the distribution of V-J combinations of the human β chain of the T-cell receptor (hTRBV) in NOD.SCID.γc(-/-) (NSG) humanized mice. We observed that numerous V-J combinations were equally distributed in the thymus and in the periphery of humanized mice compared with human references. A global analysis of the data, comparing repertoire perturbation indices in humanized NSG mice and unrelated human PBMCs, reveals that 50% of the hTRBV families significantly overlapped. Using multivariate ranking and bootstrap analyses, we found that 18% of all possible V-J combinations contributed close to 50% of the expressed diversity, with significant over-representation of BV5-J1.1+1.2 and BV6-J1.1+1.2 rearrangements. Finally, comparison of CD3(-) and CD3(+) thymocyte repertoires indicated that the observed V-J combination overlap was already present before TCR-MHC selection in the thymus. Altogether, our results show that half of the T-cell repertoire combinatorial diversity in humans is genetically determined.
在人源化小鼠中，T 细胞受体（TCR）的 T 细胞库源自不同动物中具有遗传同一性的人类前体。因此，仔细比较人源化小鼠和人类的 T 细胞库，可能会揭示遗传决定论对 T 细胞库形成的贡献。在这里，我们对 NOD.SCID.γc(-/-)（NSG）人源化小鼠的人类 TCRβ链（hTRBV）的 V-J 组合分布进行了全面评估。我们观察到，与人类参考相比，许多 V-J 组合在人源化小鼠的胸腺和外周血中分布均匀。对人源化 NSG 小鼠和无关人类 PBMC 之间的 repertoire perturbation 指数进行的全局分析表明，50%的 hTRBV 家族显著重叠。使用多元排序和自举分析，我们发现所有可能的 V-J 组合中有 18%接近 50%的表达多样性，BV5-J1.1+1.2 和 BV6-J1.1+1.2 重排显著过表达。最后，比较 CD3(-)和 CD3(+)胸腺细胞库表明，在胸腺中 TCR-MHC 选择之前，已经存在观察到的 V-J 组合重叠。总之，我们的研究结果表明，人类 T 细胞库组合多样性的一半是由遗传决定的。
