Although most patients with type 1 diabetes (T1D) retain some functional insulin-producing islet β cells at the time of diagnosis, the rate of further β cell loss varies across individuals. It is not clear what drives this differential progression rate. CD8+ T cells have been implicated in the autoimmune destruction of β cells. Here, we addressed whether the phenotype and function of autoreactive CD8+ T cells influence disease progression. We identified islet-specific CD8+ T cells using high-content, single-cell mass cytometry in combination with peptide-loaded MHC tetramer staining. We applied a new analytical method, DISCOV-R, to characterize these rare subsets. Autoreactive T cells were phenotypically heterogeneous, and their phenotype differed by rate of disease progression. Activated islet-specific CD8+ memory T cells were prevalent in subjects with T1D who experienced rapid loss of C-peptide; in contrast, slow disease progression was associated with an exhaustion-like profile, with expression of multiple inhibitory receptors, limited cytokine production, and reduced proliferative capacity. This relationship between properties of autoreactive CD8+ T cells and the rate of T1D disease progression after onset make these phenotypes attractive putative biomarkers of disease trajectory and treatment response and reveal potential targets for therapeutic intervention.

中文翻译：

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自身反应性 CD8+ T 细胞耗竭是 1 型糖尿病进展缓慢的受试者的特征。

尽管大多数 1 型糖尿病 (T1D) 患者在诊断时保留了一些功能性的产生胰岛素的胰岛 β 细胞，但 β 细胞进一步丧失的速度因人而异。目前尚不清楚是什么导致了这种不同的进展率。CD8+ T 细胞与 β 细胞的自身免疫破坏有关。在这里，我们探讨了自身反应性 CD8+ T 细胞的表型和功能是否影响疾病进展。我们使用高内涵单细胞质谱流式技术结合肽负载 MHC 四聚体染色来鉴定胰岛特异性 CD8+ T 细胞。我们应用了一种新的分析方法 DISCOV-R 来表征这些罕见的子集。自身反应性 T 细胞具有表型异质性，其表型因疾病进展速度而异。活化的胰岛特异性 CD8+ 记忆 T 细胞在 C 肽快速丧失的 T1D 受试者中普遍存在；相比之下，缓慢的疾病进展与类似疲惫的情况相关，并伴有多种抑制性受体的表达、细胞因子的产生有限和增殖能力降低。自身反应性 CD8+ T 细胞的特性与发病后 T1D 疾病进展率之间的这种关系使这些表型成为疾病轨迹和治疗反应的假定生物标志物，并揭示了治疗干预的潜在目标。