Prevalent CD8+ T cell response against one peptide/MHC complex in autoimmune diabetes
Prevalent CD8+ T cell response against one peptide/MHC complex in autoimmune diabetes
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DOI：
10.1073/pnas.96.16.9311
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发表时间：
1999-08-03
影响因子：
11.1
通讯作者：
Santamaria, P
中科院分区：
文献类型：
--
作者：
Anderson, B;Park, BJ;Santamaria, P
非肥胖糖尿病（NOD）小鼠中的自发性自身免疫性糖尿病是针对胰腺β细胞的CD 4（+）和CD 8（+）T细胞依赖性自身免疫过程的结果。CD 8（+）T细胞在糖尿病的发生和发展中起着关键作用，但其抗原库的特异性和多样性仍不清楚。在这里，我们定义了一个肽模拟表位的结构，该表位增强了致糖尿病H-2K（d）限制性CD 8（+）T细胞特异性的增殖、细胞因子分泌、分化和细胞毒性。（NY8.3）使用T细胞受体α CD 8（+）T细胞频繁表达的（TCR α）重排，该细胞从NOD小鼠最早的胰岛病变中增殖（V α 17-J α 42元件，通常由N区序列M-R-D/E连接）。用该模拟表位刺激来自单链8.3-TCR β转基因NOD螨的脾CD 8（+）T细胞，导致携带内源性来源的TCR α链的T细胞优先扩增，所述TCR α链与其胰岛相关的CD 8（+）T细胞所使用的TCR α链相同，其也与8，3-TCR α序列相同。使用来自非转基因NOD小鼠的胰岛衍生的CD 8（+）T细胞克隆作为效应物和肽脉冲H-2K（d）转染的RMA-S细胞作为靶细胞的细胞毒性测定表明，在NOD小鼠中，募集到胰岛的近一半的CD 8（+）T细胞特异性识别相同的肽/H-2K（d）复合物，这项工作表明，β细胞反应性CD 8（+）T细胞对单一肽/MHC复合物产生普遍反应，并为自身免疫性糖尿病中的CD 8（+）T细胞提供一种肽配体。
Spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice is the result of a CD4(+) and CD8(+) T cell-dependent autoimmune process directed against the pancreatic beta cells. CD8(+) T cells play a critical role in the initiation and progression of diabetes, but the specificity and diversity of their antigenic repertoire remain unknown. Here, se define the structure of a peptide mimotope that elicits the proliferation, cytokine secretion, differentiation, and cytotoxicity of a diabetogenic H-2K(d)-restricted CD8(+) T cell specificity (NY8.3) that uses a T cell receptor alpha (TCR alpha) rearrangement frequently expressed by CD8(+) T cells propagated from the earliest insulitic lesions of NOD mice (V alpha 17-J alpha 42 elements, often joined by the N-region sequence M-R-D/E). Stimulation of splenic CD8(+) T cells from single-chain 8.3-TCR beta-transgenic NOD mite with this mimotope leads to preferential expansion of T cells bearing an endogenously derived TCR alpha chain identical to the one used by their islet-associated CD8(+) T cells, which is also identical to the 8,3-TCR alpha sequence. Cytotoxicity assays using islet-derived CD8(+) T cell clones from nontransgenic NOD mice as effecters and peptide-pulsed H-2K(d)-transfected RMA-S cells as targets indicate that nearly half of the CD8(+) T cells recruited to islets in NOD mice specifically recognize the same peptide/H-2K(d) complex, This work demonstrates that beta cell-reactive CD8(+) T cells mount a prevalent response against a single peptide/MHC complex and provides one peptide ligand for CD8(+) T cells in autoimmune diabetes.