Li Li, He Qiuming, Garland Alaina, Yi Zuoan, Aybar Lydia T, Kepler Thomas B, Frelinger Jeffrey A, Wang Bo, Tisch Roland
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
J Immunol. 2009 Dec 1;183(11):7585-91. doi: 10.4049/jimmunol.0901587. Epub 2009 Nov 16.
Type 1 diabetes is an autoimmune disease mediated by beta cell-specific CD4(+) and CD8(+) T cells. Tracking beta cell-specific T cells is one approach to monitor the diabetogenic response in at risk or diabetic individuals. Such analyses, however, are limited to PBL because T cells infiltrating the pancreatic islets are normally inaccessible. A key issue is whether peripheral beta cell-specific T cells accurately reflect those cells infiltrating the target tissue. We investigated the properties of CD4(+) T cells specific for a mimetic epitope recognized by the BDC2.5 clonotypic TCR in NOD mice. Soluble IA(g7)-Ig (sIA(g7)-Ig) multimer complexes covalently linked to a mimetic BDC peptide (sIA(g7)-mBDC) were used to identify or isolate CD4(+) T cells from PBL and the islets of NOD mice. A temporal increase in sIA(g7)-mBDC binding (g7-mBDC(+)) T cells corresponding with the progression of beta cell autoimmunity was detected in both PBL and islets in NOD female mice. In contrast to T cells in PBL, however, the majority of islet g7-mBDC(+) T cells exhibited a type 1 phenotype, and mediated diabetes upon transfer into NOD.scid recipients. TCR-beta and CDR-beta gene usage of single islet-infiltrating g7-mBDC(+) CD4(+) T cells from individual NOD mice showed a restricted repertoire dominated by one or two clones typically expressing TCR beta-chain variable TRBV-15. In contrast, a distinct and diverse TCR repertoire was detected for PBL-derived g7-mBDC(+) T cells. These results demonstrate that PBL and islet CD4(+) T cells specific for a given beta cell epitope can differ regarding pathogenicity and TCR repertoire.
1型糖尿病是一种由β细胞特异性CD4(+)和CD8(+) T细胞介导的自身免疫性疾病。追踪β细胞特异性T细胞是监测高危或糖尿病个体致糖尿病反应的一种方法。然而，此类分析仅限于外周血淋巴细胞（PBL），因为浸润胰岛的T细胞通常难以获取。一个关键问题是外周β细胞特异性T细胞是否能准确反映浸润靶组织的细胞。我们研究了NOD小鼠中被BDC2.5克隆型TCR识别的模拟表位特异性CD4(+) T细胞的特性。与模拟BDC肽共价连接的可溶性IA(g7)-Ig（sIA(g7)-Ig）多聚体复合物（sIA(g7)-mBDC）用于从NOD小鼠的PBL和胰岛中鉴定或分离CD4(+) T细胞。在NOD雌性小鼠的PBL和胰岛中均检测到与β细胞自身免疫进展相对应的sIA(g7)-mBDC结合（g7-mBDC(+)）T细胞的时间性增加。然而，与PBL中的T细胞不同，大多数胰岛g7-mBDC(+) T细胞表现出1型表型，并在转移至NOD.scid受体后介导糖尿病。来自个体NOD小鼠的单个胰岛浸润g7-mBDC(+) CD4(+) T细胞的TCR-β和CDR-β基因使用情况显示，其库有限，主要由通常表达TCR β链可变区TRBV-15的一两个克隆主导。相比之下，在源自PBL的g7-mBDC(+) T细胞中检测到明显不同且多样的TCR库。这些结果表明，针对给定β细胞表位的PBL和胰岛CD4(+) T细胞在致病性和TCR库方面可能存在差异。
