Inhibition of altered peptide ligand-mediated antagonism of human GAD65-responsive CD4+ T cells by non-antagonizable T cells
Inhibition of altered peptide ligand-mediated antagonism of human GAD65-responsive CD4+ T cells by non-antagonizable T cells
复制标题
DOI：
10.1002/eji.200425535
复制
发表时间：
2004-12-01
影响因子：
5.4
通讯作者：
Nepom, GT
中科院分区：
文献类型：
--
作者：
Gebe, JA;Masewicz, SA;Nepom, GT
来自T细胞反应性自身抗原的改变的肽配体已被证明是自身免疫动物模型中的保护性治疗剂。在这项研究中，我们鉴定了几种来自1型糖尿病相关自身抗原人谷氨酸脱羧酶65（hGAD 65）表位的改变的肽配体，这些肽配体能够拮抗来自糖尿病个体的一组人CD 4（+）GAD 65（555-567）应答性T细胞克隆的子集。虽然没有改变的肽配体能够拮抗T细胞组中的所有六个克隆，但是位于TCR接触p5位置的位置561处的异亮氨酸至甲硫氨酸的单取代肽能够拮抗六个hGAD 65响应性克隆中的五个。在混合的T细胞培养系统中，我们观察到改变的肽配体介导的拮抗作用以剂量依赖性方式被非拮抗性hGAD 65（555-567）应答性T细胞的存在抑制。从混合T细胞培养物中存在的细胞因子的分析，白细胞介素-2足以抑制改变的肽配体诱导的拮抗作用。通过不可拮抗的T细胞抑制改变的肽配体介导的自身抗原应答性T细胞的拮抗作用在以T细胞拮抗作用为目标的改变的肽配体治疗中具有意义。
Altered peptide ligands derived from T cell-reactive self antigens have been shown to be protective therapeutic agents in animal models of autoimmunity. In this study we identified several altered peptide ligands derived from the type 1 diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65) epitope that were capable of antagonizing a subset of a panel of human CD4(+) GAD65 (555-567)-responsive T cell clones derived from a diabetic individual. While no altered peptide ligand was able to antagonize all six clones in the T cell panel, a single-substituted peptide of isoleucine to methionine at position 561, which resides at the TCR contact p5 position, was able to antagonize five out of the six hGAD65-responsive clones. In a mixed T cell culture system we observed that altered peptide ligand-mediated antagonism is inhibited in a dose-dependent manner by the presence of nonantagonizable hGAD65 (555-567)-responsive T cells. From an analysis of the cytokines present in the mixed T cell cultures, interleukin-2 was sufficient to inhibit altered peptide ligand-induced antagonism. The inhibition of altered peptide ligand-mediated antagonism of self-antigen-responsive T cells by non-antagonizable T cells has implications in altered peptide ligand therapy where T cell antagonism is the goal.