Department of Cellular and Molecular Immunology, University of Göttingen Medical School, Germany.
J Immunol. 2010 Aug 15;185(4):2285-94. doi: 10.4049/jimmunol.1000462. Epub 2010 Jul 19.
Diabetes-prone BioBreeding (DP-BB) rats spontaneously develop type 1 diabetes mellitus (T1DM) on grounds of their MHC haplotype RT1(u) and a point mutation in the Gimap5 gene. In this study, we report that DP-BB rats exhibit an increasingly severe imbalance, in particular between Th17 and regulatory T (T(reg)) cells, within the first months of age. This can be assigned to an excess in effector T cells because neither the percentage nor the function of the T(reg) cells is compromised. Flow cytometric analysis of Vbeta segment usage and CDR3 spectratyping further suggest that the disturbed repertoire of peripheral T cells may also contribute to the development of T1DM in DP-BB rats. Importantly, expansion of T(reg) cells in vivo by means of a CD28 superagonistic Ab as well as adoptive transfer of T(reg) cells efficiently interferes with the development of T1DM in DP-BB rats, whereas treatment with conventional Th cells does not afford protection. Using a newly generated strain of enhanced GFP transgenic rats, we could further demonstrate that the transferred T(reg) cells persist in the recipient rats for several months and partially correct the imbalance between Th17 and T(reg) cells. Thus, our data support the hypothesis that unchecked effector T cell action and a disturbed T cell repertoire contribute to the development of T1DM in DP-BB rats, which may also have implications for a better understanding of the human disease.
易患糖尿病的 BioBreeding（DP-BB）大鼠由于其 MHC 单倍型 RT1(u)和 Gimap5 基因的点突变，自发地发展为 1 型糖尿病（T1DM）。在这项研究中，我们报告说 DP-BB 大鼠在生命的头几个月内表现出越来越严重的失衡，特别是在 Th17 和调节性 T（Treg）细胞之间。这可以归因于效应 T 细胞的过剩，因为 Treg 细胞的百分比和功能都没有受到损害。Vbeta 片段使用和 CDR3 谱型分析的流式细胞术分析进一步表明，外周 T 细胞紊乱的库也可能有助于 DP-BB 大鼠 T1DM 的发展。重要的是，通过 CD28 超激动性 Ab 体内扩增 Treg 细胞以及过继转移 Treg 细胞可有效地干扰 DP-BB 大鼠 T1DM 的发展，而传统 Th 细胞的治疗则不能提供保护。使用新生成的增强 GFP 转基因大鼠品系，我们进一步证明了转移的 Treg 细胞在受体大鼠中可存在数月，并部分纠正 Th17 和 Treg 细胞之间的失衡。因此，我们的数据支持这样的假设，即不受控制的效应 T 细胞作用和紊乱的 T 细胞库有助于 DP-BB 大鼠 T1DM 的发展，这也可能对更好地理解人类疾病有意义。
