INSERM, Unité 1043, F-31300 Toulouse, France.
J Immunol. 2012 Sep 15;189(6):3140-9. doi: 10.4049/jimmunol.1103111. Epub 2012 Aug 17.
An increase in IL-17-producing CD8+ T (Tc17) cells has been reported in the peripheral blood of children with recent onset type 1 diabetes (T1D), but their contribution to disease pathogenesis is still unknown. To directly study the pathogenic potential of β cell-specific Tc17 cells, we used an experimental model of T1D based on the expression of the neo-self Ag hemagglutinin (HA) in the β cells of the pancreas. When transferred alone, the IL-17-producing HA-specific CD8+ T cells homed to the pancreatic lymph nodes without causing any pancreatic infiltration or tissue destruction. When transferred together with small numbers of diabetogenic HA-specific CD4+ T cells, a strikingly different phenotype developed. Under these conditions, Tc17 cells sustained disease progression, driving the destruction of β-islet cells, causing hyperglycemia and ultimately death. Disease progression did not correlate with functional or numerical alterations among the HA-specific CD4+ T cells. Rather, the transferred CD8+ T cells accumulated in the pancreatic islets and a considerable fraction converted, under the control of IL-12, to an IFN-γ-producing phenotype. Our data indicate that Tc17 cells are not diabetogenic but can potentiate a Th1-mediated disease. Plasticity of the Tc17 lineage is associated with transition to overt disease in this experimental model of T1D.
在近期发病的 1 型糖尿病（T1D）患儿的外周血中，已报道白细胞介素-17（IL-17）产生的 CD8+T（Tc17）细胞增加，但它们对疾病发病机制的贡献仍不清楚。为了直接研究β细胞特异性 Tc17 细胞的致病潜力，我们使用了一种基于胰腺β细胞中新型自身抗原血凝素（HA）表达的 T1D 实验模型。当单独转导时，产生 IL-17 的 HA 特异性 CD8+T 细胞归巢到胰腺淋巴结，而不会引起任何胰腺浸润或组织破坏。当与少量致糖尿病的 HA 特异性 CD4+T 细胞一起转导时，会出现截然不同的表型。在这些条件下，Tc17 细胞维持疾病进展，驱动β胰岛细胞的破坏，导致高血糖，最终导致死亡。疾病进展与 HA 特异性 CD4+T 细胞的功能或数量变化无关。相反，转导的 CD8+T 细胞在胰腺胰岛中积累，并且在 IL-12 的控制下，相当一部分细胞转化为产生 IFN-γ的表型。我们的数据表明，Tc17 细胞不是致糖尿病的，但可以增强 Th1 介导的疾病。在这种 T1D 实验模型中，Tc17 细胞系的可塑性与向显性疾病的转变有关。
