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

点击翻译按钮获取中文摘要

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.