Autoreactive V alpha 14 T cell and their contribution of the development of autoimmune diseases

我们发现，携带由Valpha 14 Jalpha 281编码的具有一个碱基N区的恒定TCR的同源CD 4-/CD 8- T细胞在外周中高度占优势（脾中2-3%）。令人惊讶的是，在所有实验室品系中，无论MHC单倍型如何，以及在一些野生小鼠亚种中，均质Valpha 14 TCR的高表达是普遍现象。在新生儿阶段，大多数Valpha 14 ^+ TCR与Jalpha而不是Jalpha 281相关，然后不变的Valpha 14 Jalpha 281 TCR表达的频率随时间增加，并在出生后约5-8周达到最大值。正常胸腺和无胸腺小鼠均存在Valpha 14 Jalpha 281 TCR的优势表达，表明同种的Valpha 14 Jalpha 281 T细胞在无胸腺影响的情况下在外周被正向选择，它们的VJ连接对于正向选择是重要的。我们还证明了Val pha 14 ^+ TCR基因重排发生在胸腺外部位，如骨髓、肝脏和肠，因为频繁的非生产性Val pha 14 TCR产物和Val pha 14-Jalpha 281基因介导的环状DNA信号序列是胸腺外组织而不是胸腺中TCR重排的结果，表明Val pha 14 Jalpha 281 T细胞的胸腺外发育。在无胸腺小鼠的胸腺外组织中未检测到由已知胸腺依赖性的Valpha1.1-Jalpha 281产生的环状DNA。此外，不变的Valpha 14 TCR表达的减少与自身免疫性疾病的发展密切相关。这表明了不变的Valpha 14 Jalpha 281 T细胞在调节抗自身应答中的关键作用。

We found that a homogenous CD4-/CD8- T cell bearing invariant TCR encoded by Valpha14Jalpha281 with a one-base N-region is highly dominated in the periphery (2-3% in spleen). Surprisingly the high expression of the homogenous Valpha14 TCR is a general phenomenon in all laboratory strains irrespective of MHC haplotypes and in some wild mouse subspecies. The majority of Valpha14^+ TCR are associated with Jalpha other than Jalpha281 at the neonatal stage and then the frequency of invariant Valpha14Jalpha281 TCR expression increases with time and reached a maximum at around 5-8 weeks after birth. The dominant expression of Valpha14Jalpha281 TCR is found both in euthymic and athymic mice.These results indicate that homogenous Valpha14Jalpha281 T cells are positively selected in the periphery without thymic influence and that their VJ junction is important for the positive selection. We also demonstrate that Valpha14^+ TCR gene rearrangements take place in extrathymic sites, such as bone marrow, liver, and intestine, since frequent nonproductive Valpha14 TCR products and Valpha14-Jalpha281 gene mediated signal sequences of the circular DNA are detected as a result of TCR rearrangements in extrathymic tissues rather than the thymus, indicating the extrathymic development of Valpha14Jalpha281 T cells. No circular DNA generated by Valpha1.1-Jalpha281 which is known to be thymus-dependent was detected in extrathymic tissues of athymic mice. Moreover, the decrease in the invariant Valpha14 TCR expression was tightly correlated with the development of autoimmune diseases. This suggests the crucial role of the invariant Valpha14Jalpha281 T cells in the regulation of anti-self responses.