CD57 CD8 T cells, also referred as effector memory cells, are implicated in various conditions including tumor immunity, virus immunity, and most recently with autoimmunity. However, their roles in the progression and remission of T1D are still unclear. Here, we noted an increase in peripheral CD57 CD8 T cells in a T1D patient harboring an activator of transcription 3 (STAT3) mutation. Our in-depth study on the role of CD57 CD8 T cells within a T1D patient cohort revealed that these cells undergo significant compositional shifts during the disease's progression. Longitudinal cohort data suggested that CD57 CD8 T cell prevalence may be a harbinger of β-cell function decline in T1D patients. Characterized by robust cytotoxic activity, heightened production of pro-inflammatory cytokines, and increased intracellular glucose uptake, these cells may be key players in the pathophysiology of T1D. Moreover, in vitro assays showed that the CXCL12-CXCR4 axis promotes the expansion and function of CD57 CD8 T cells via Erk1/2 signaling. Notably, the changes of serum CXCL12 concentrations were also found in individuals during the peri-remission phase of T1D. Furthermore, treatment with the CXCR4 antagonist LY2510924 reduced the immunological infiltration of CD57 CD8 T cells and mitigated hyperglycemia in a STZ-induced T1D mouse model. Taken together, our work has uncovered a novel role of the CXCL12-CXCR4 axis in driving CD57 CD8 T cells responses in T1D, and presented a promising therapeutic strategy for delaying the onset and progression of diabetes.

中文翻译：

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CXCL12-CXCR4 在 1 型糖尿病进展中介导 CD57+ CD8+ T 细胞反应

CD57 CD8 T 细胞，也称为效应记忆细胞，与多种疾病有关，包括肿瘤免疫、病毒免疫以及最近的自身免疫。然而，它们在 T1D 进展和缓解中的作用仍不清楚。在这里，我们注意到携带转录激活剂 3 (STAT3) 突变的 T1D 患者外周 CD57 CD8 T 细胞增加。我们对 T1D 患者群体中 CD57 CD8 T 细胞作用的深入研究表明，这些细胞在疾病进展过程中经历了显着的组成变化。纵向队列数据表明，CD57 CD8 T 细胞的流行可能是 T1D 患者 β 细胞功能下降的先兆。这些细胞具有强大的细胞毒活性、促炎细胞因子产生增加和细胞内葡萄糖摄取增加的特点，可能是 T1D 病理生理学的关键参与者。此外，体外测定表明，CXCL12-CXCR4 轴通过 Erk1/2 信号传导促进 CD57 CD8 T 细胞的扩增和功能。值得注意的是，在 T1D 的围缓解期个体中也发现了血清 CXCL12 浓度的变化。此外，在 STZ 诱导的 T1D 小鼠模型中，使用 CXCR4 拮抗剂 LY2510924 治疗可减少 CD57 CD8 T 细胞的免疫浸润并减轻高血糖。总而言之，我们的工作揭示了 CXCL12-CXCR4 轴在驱动 T1D 中 CD57 CD8 T 细胞反应中的新作用，并提出了一种有前途的延缓糖尿病发病和进展的治疗策略。