Peptide-activated double-negative T cells can prevent autoimmune type-1 diabetes development
Peptide-activated double-negative T cells can prevent autoimmune type-1 diabetes development
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DOI：
10.1002/eji.200636991
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发表时间：
2007-08-01
影响因子：
5.4
通讯作者：
Zhang, Li
中科院分区：
文献类型：
--
作者：
Ford, Megan S.;Chen, Wenhao;Zhang, Li
由于调节性T细胞的成熟、活化、分化和功能缺陷，可能导致自身免疫性疾病的发生。先前的研究表明，暴露于供体抗原激活外周TCR α - β (+)CD3(+)CD4(-)CD8(-)NK1.1（-）双阴性（DN） T细胞，特异性抑制抗供体T细胞，提高同种异体和异种供体皮肤和心脏移植的存活率。然而，dnt细胞在预防T细胞介导的自身免疫性疾病中的作用尚不清楚。在这里，我们分析了DN T细胞识别自身MHC上表达的肽的能力，并使用P14小鼠模型来抑制肽反应性CD8(+) T细胞，P14小鼠模型表达了一种转基因TCR，特异性针对自身MHC I-D-b类上呈现的gp33肽。我们发现，与未治疗的小鼠相比，注射gp33肽导致DN增加，淋巴结CD8+ T细胞数量减少。注射gp33，而不注射tcr -非特异性AV肽，增加了DN T细胞上T细胞活化标志物的表达。此外，gp33激活的DN T细胞通过在体外以抗原特异性方式杀死活化的CD8(+) T细胞来抑制同基因CD8(+) T细胞的增殖。此外，转移gp33激活的DN T细胞可以抑制自身免疫性糖尿病的发展，这表明DN T细胞可能为T细胞介导的自身免疫性疾病提供了一种新的治疗方法。
Autoimmune diseases may develop because of defective maturation, activation, differentiation and function of regulatory T cells. Previous studies have shown that exposure to donor antigen activates peripheral TCR alpha beta(+)CD3(+)CD4(-)CD8(-)NK1.1(-), double-negative (DN) T cells, which specifically suppress anti-donor T cells and enhance survival of skin and heart grafts from allogeneic and xenogeneic donors. However, the role of DN T cells in preventing T cell-mediated autoimmune disease is unknown. Here, we analyzed the ability of DN T cells to recognize peptides expressed on self MHC and to suppress peptide-reactive CD8(+) T cells, using the P14 mouse model that expresses a transgenic TCR specific for gp33 peptide presented on self MHC class I-D-b. We found that injection of gp33 peptide resulted in increased DN and decreased CD8+ T cell numbers in the lymph nodes when compared to untreated mice. Injection of gp33, but not TCR-non-specific AV peptide, increased expression of T cell activation markers on DN T cells. Moreover, gp33-activated DN T cells suppressed proliferation of syngeneic CD8(+) T cells via killing activated CD8(+) T cells in an antigen-specific fashion in vitro. Furthermore, transferring gp33-activated DN T cells inhibited the development of autoimmune diabetes, suggesting that DN T cells may provide a novel therapy for T cellmediated autoimmune diseases.