Poussier Philippe, Ning Terri, Murphy Trista, Dabrowski Dominika, Ramanathan Sheela
Sunnybrook and Women's College Health Sciences Centre, Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
J Immunol. 2005 Apr 1;174(7):4081-9. doi: 10.4049/jimmunol.174.7.4081.
One of the BB rat diabetes (diabetes mellitus (DM)) susceptibility genes is an Ian5 mutation resulting in premature apoptosis of naive T cells. Impaired differentiation of regulatory T cells has been suggested as one possible mechanism through which this mutation contributes to antipancreatic autoimmunity. Using Ian5 congenic inbred rats (wild-type (non-lyp BB) and mutated (BB)), we assessed the development of BB regulatory CD8(-)4(+)25(+)T cells and their role in the pathogenesis of DM. BB rats have normal numbers of functional CD8(-)4(+)25(+)Foxp3(+) thymocytes. The proportion of CD25(+) cells among CD8(-)4(+) recent thymic emigrants is also normal while it is increased among more mature CD8(-)4(+) T cells. However, BB CD8(-)4(+)25(+)Foxp3(+) thymocytes fail to undergo homeostatic expansion and survive upon transfer to nude BB rats while Foxp3 expression is reduced in mature CD8(-)4(+)25(+) T cells suggesting that these cells are mostly activated cells. Consistent with this interpretation, peripheral BB CD8(-)4(+)25(+) T cells do not suppress anti-TCR-mediated activation of non-lyp BB CD8(-)4(+)25(-) T cells but rather stimulate it. Furthermore, adoptive transfer of unfractionated T cells from diabetic BB donors induces DM in 71% of the recipients while no DM occurred when donor T cells are depleted of CD8(-)4(+)25(+) cells. Adoptive transfer of 10(6) regulatory non-lyp BB CD8(-)4(+)25(+) T cells to young BB rats protects the recipients from DM. Taken together, these results demonstrate that the BB rat Ian5 mutation alters the survival and function of regulatory CD8(-)4(+)25(+) T cells at the post-thymic level, resulting in clonal expansion of diabetogenic T cells among peripheral CD8(-)4(+)25(+) cells.
BB大鼠糖尿病（糖尿病（DM））易感性基因之一是Ian5突变，该突变导致幼稚T细胞过早凋亡。调节性T细胞分化受损被认为是这种突变导致抗胰腺自身免疫的一种可能机制。我们使用Ian5同源近交系大鼠（野生型（非lyp BB）和突变型（BB）），评估了BB调节性CD8(-)4(+)25(+)T细胞的发育及其在DM发病机制中的作用。BB大鼠功能性CD8(-)4(+)25(+)Foxp3(+)胸腺细胞数量正常。CD8(-)4(+)近期胸腺迁出细胞中CD25(+)细胞的比例也正常，而在更成熟的CD8(-)4(+)T细胞中则增加。然而，BB CD8(-)4(+)25(+)Foxp3(+)胸腺细胞在转移到裸BB大鼠后无法进行稳态扩增并存活，而在成熟的CD8(-)4(+)25(+)T细胞中Foxp3表达降低，这表明这些细胞大多是活化细胞。与这种解释一致的是，外周BB CD8(-)4(+)25(+)T细胞不抑制抗TCR介导的非lyp BB CD8(-)4(+)25(-)T细胞的活化，反而刺激它。此外，来自糖尿病BB供体的未分级T细胞的过继转移在71%的受体中诱导了DM，而当供体T细胞耗尽CD8(-)4(+)25(+)细胞时则未发生DM。将10(6)个调节性非lyp BB CD8(-)4(+)25(+)T细胞过继转移到年轻BB大鼠中可保护受体免受DM侵害。综上所述，这些结果表明，BB大鼠Ian5突变在胸腺后水平改变了调节性CD8(-)4(+)25(+)T细胞的存活和功能，导致外周CD8(-)4(+)25(+)细胞中致糖尿病T细胞的克隆扩增。
