Burnet postulated that the diversity of T-cell receptors (TCR) allows T cells to protect against the development of cancers that display antigens with a similar, seemingly endless diversity. To test this hypothesis, we developed a strategy in which a single breeding pair of mice gives rise to four groups of sibling mice. Three of the four groups had a similar number of CD8+ T cells, but TCR diversity was either broad, significantly reduced, or absent when expressing only one type of TCR. The fourth group had no T cells. All mice shared the same housing, and, therefore, their microbial environment was similar. Only slight differences in the intestinal flora were observed under these conditions. An undisturbed broad TCR repertoire was required for the rejection of inoculated cancers displaying the natural antigenic heterogeneity of primary tumors, whereas even one type of TCR was sufficient to protect against artificial cancers stably expressing cognate antigens. The three groups of mice with limited or no TCR repertoire showed an increased risk of developing primary tumors after chemical induction. However, the risk of early death or morbidity in these cohorts of mice was significantly higher than in mice with a diverse TCR repertoire, and it remains unknown whether mice with reduced TCR diversity, who died early without cancer, would have developed tumors with higher, lower, or equal probability after induction. Together, TCR diversity seems crucial to overcome the natural genetic instability of cancers and their antigenic heterogeneity, which impacts the design of cellular therapies.

中文翻译：

---

TCR多样性对移植或化学诱导肿瘤发展的影响。

Burnet推测，T细胞受体（TCR）的多样性使T细胞可以保护其发展出具有相似，看似无穷无尽的抗原的抗原。为了检验这个假设，我们开发了一种策略，其中一对繁殖的小鼠产生了四组同胞小鼠。四组中的三组具有相似数量的CD8 + T细胞，但仅表达一种类型的TCR时，TCR多样性宽泛，显着降低或不存在。第四组没有T细胞。所有小鼠都共享相同的外壳，因此它们的微生物环境相似。在这些条件下，仅观察到肠道菌群的细微差异。表现出原发性肿瘤天然抗原异质性的已接种癌症的排斥反应需要一个不受干扰的广泛TCR库，而即使是一种类型的TCR也足以抵御稳定表达同源抗原的人工癌症。三组具有有限或无TCR功能库的小鼠在化学诱导后出现原发性肿瘤的风险增加。但是，这些组小鼠的早期死亡或发病的风险显着高于具有多种TCR组成成分的小鼠，并且尚不清楚是否患有TCR多样性降低的小鼠早死于无癌症的小鼠会发展出更高的肿瘤发生率，归纳后更低或相等的概率。总之，TCR多样性似乎对于克服癌症的自然遗传不稳定性及其抗原异质性至关重要，这会影响细胞疗法的设计。