Exploring the induction of preproinsulin-specific Foxp3(+) CD4(+) Treg cells that inhibit CD8(+) T cell-mediated autoimmune diabetes by DNA vaccination.
Exploring the induction of preproinsulin-specific Foxp3(+) CD4(+) Treg cells that inhibit CD8(+) T cell-mediated autoimmune diabetes by DNA vaccination.
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DOI：
10.1038/srep29419
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发表时间：
2016-07-11
影响因子：
4.6
通讯作者：
Schirmbeck R
中科院分区：
文献类型：
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作者：
Stifter K;Schuster C;Schlosser M;Boehm BO;Schirmbeck R
DNA疫苗接种是诱导效应T细胞以及调节性Foxp 3 + CD 25 + CD 4 + Treg细胞并抑制自身免疫性疾病如1型糖尿病的有希望的策略。关于促进Treg细胞而不是自身反应性效应CD 8 + T细胞的引发的抗原要求知之甚少。我们已经证明，将表达前胰岛素原（ppins）的pCI/ppins载体注射到PD-1或PD-L1缺陷小鼠中诱导了Kb/A12-21单特异性CD 8 + T细胞和自身免疫性糖尿病。pCI/ppinsΔA12-21载体（缺乏关键Kb/A12-21表位）不诱导自身免疫性糖尿病，但引起系统性Foxp 3 + CD 25 + Treg细胞免疫，其通过随后注射致糖尿病性pCI/ppins抑制糖尿病诱导。在接种疫苗/ppins致敏小鼠的Foxp 3 + CD 25 + Treg细胞群中，TGF-β表达显著增强。通过抗CD 25抗体处理在接种疫苗的/ppins致敏的小鼠中消融Treg细胞消除了疫苗的保护作用，并且使得能够通过pCI/ppins诱导糖尿病。将Treg细胞从接种/ppins的小鼠中连续转移到PD-L1−/−宿主中有效抑制了pCI/ppins诱导的糖尿病。我们将Treg刺激结构域缩小到15个残基的ppins 76 -90肽。因此，疫苗诱导的Treg细胞在该糖尿病模型中控制从头引发的自身反应性效应CD 8 + T细胞中起关键作用。
DNA vaccination is a promising strategy to induce effector T cells but also regulatory Foxp3+ CD25+ CD4+ Treg cells and inhibit autoimmune disorders such as type 1 diabetes. Little is known about the antigen requirements that facilitate priming of Treg cells but not autoreactive effector CD8+ T cells. We have shown that the injection of preproinsulin (ppins)-expressing pCI/ppins vector into PD-1- or PD-L1-deficient mice induced Kb/A12-21-monospecific CD8+ T cells and autoimmune diabetes. A pCI/ppinsΔA12-21 vector (lacking the critical Kb/A12-21 epitope) did not induce autoimmune diabetes but elicited a systemic Foxp3+ CD25+ Treg cell immunity that suppressed diabetes induction by a subsequent injection of the diabetogenic pCI/ppins. TGF-β expression was significantly enhanced in the Foxp3+ CD25+ Treg cell population of vaccinated/ppins-primed mice. Ablation of Treg cells in vaccinated/ppins-primed mice by anti-CD25 antibody treatment abolished the protective effect of the vaccine and enabled diabetes induction by pCI/ppins. Adoptive transfer of Treg cells from vaccinated/ppins-primed mice into PD-L1−/− hosts efficiently suppressed diabetes induction by pCI/ppins. We narrowed down the Treg-stimulating domain to a 15-residue ppins76–90 peptide. Vaccine-induced Treg cells thus play a crucial role in the control of de novo primed autoreactive effector CD8+ T cells in this diabetes model.