The level of peptide-MHC complex determines the susceptibility to autoimmune diabetes: studies in HEL transgenic mice
The level of peptide-MHC complex determines the susceptibility to autoimmune diabetes: studies in HEL transgenic mice
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DOI：
10.1002/1521-4141(200112)31:12
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发表时间：
2001-12-01
影响因子：
5.4
通讯作者：
Unanue, ER
中科院分区：
文献类型：
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作者：
DiPaolo, RJ;Unanue, ER
我们报告了自发发展自身免疫性糖尿病的小鼠模型：3A 9 T细胞受体（TCR）转基因小鼠，其含有在MHC II类I-A（k）分子的背景下识别52-61家族的鸡蛋白溶菌酶（HEL）肽的T细胞，与ILK 3小鼠交配，ILK 3小鼠通过大鼠胰岛素启动子（RIP）表达HEL蛋白。尽管ILK 3小鼠中的3A 9 T细胞部分耐受，但在20周龄时，64%的3A 9 xILK 3小鼠中发生自发性糖尿病。我们提供的证据表明，来自胰腺周围淋巴结的APC具有大量的肽-MHC复合物，并刺激3A 9 T细胞。我们还报道了HEL从β细胞到APC的交叉呈递比可溶性HEL的呈递效率高26倍。我们先前报道了生物化学安全范围，基于观察到初始3A 9 T细胞的活化需要比3A 9胸腺细胞缺失所需的多100倍的肽-MHC复合物。我们推测，自体肽-MHC复合物的高局部密度可能是导致自身反应性CD 4 T细胞活化的决定因素，因此，导致自身免疫的发展。
We report a mouse model for the spontaneous development of autoimmune diabetes: the 3A9 Tcell receptor (TCR) transgenic mouse, which contains T cells that recognize the 52-61 family of hen egg-white lysozyme (HEL) peptides in the context of MHC class II I-A(k) molecules, was bred to the ILK3 mouse, that expresses HEL protein via the rat insulin promoter (RIP). Despite partial tolerance of 3A9 T cells in ILK3 mice, spontaneous diabetes developed in 64% of 3A9xILK3 mice by 20 weeks of age. We provide evidence that APC from peripancreatic nodes have a large content of peptide-MHC complex and stimulate 3A9 T cells. We also report that cross presentation of HEL from beta cells to APC is 26-fold more efficient than presentation of soluble HEL. We previously reported on a biochemical margin of safety, based on the observation that activation of naive 3A9 T cells required 100-fold more peptide-MHC complexes than required for deletion of 3A9 thymocytes. We speculate that the high local density of autologous peptide-MHC complexes can be a determining factor that leads to the activation of autoreactive CD4 T cells and, consequently, to the development of autoimmunity.