Department of Pathology, University of Iowa Health Care, Iowa City, IA, United States.
Front Immunol. 2020 Oct 28;11:568630. doi: 10.3389/fimmu.2020.568630. eCollection 2020.
Autoimmune diseases are characterized by regulatory deficit in both the CD4+ and CD8+ T-cell compartments. We have shown that CD8+ T-cells associated with acute relapse of multiple sclerosis are significantly deficient in their immune suppressive ability. We hypothesized that distinct CD8+ cytotoxic T-cell (Tc) lineages, determined by cytokine milieu during naïve T-cell differentiation, may harbor differential ability to suppress effector CD4+ T-cells. We differentiated purified human naïve CD8+ T-cells toward Tc0 (media control), Tc1 and Tc17 lineages. Using flow cytometric suppression assays, we observed that Tc0 and Tc17 cells had similar suppressive ability. In contrast, Tc1 cells showed significant loss of suppressive ability against CD4+ T-cells and -differentiated Th0, Th1 and Th17 cells. Of note, Tc1 cells were also suboptimal in suppressing CD4-induced acute xenogeneic graft versus host disease (xGVHD) . Tc subtypes derived under various cytokine combinations revealed that IL-12-containing conditions resulted in less suppressive cells exhibiting dysregulated cytotoxic degranulation. RNA sequencing transcriptome analyses indicated differential regulation of inflammatory genes and enrichment in GM-CSF-associated pathways. These studies provide insights into the role of T-cell differentiation in CD8 suppressive biology and may reveal therapeutically targetable pathways to reverse suppressive deficit during immune-mediated disease.
自身免疫性疾病的特征是 CD4+和 CD8+T 细胞区室的调节缺陷。我们已经表明，与多发性硬化症急性复发相关的 CD8+T 细胞在其免疫抑制能力方面明显不足。我们假设，在幼稚 T 细胞分化过程中由细胞因子微环境决定的不同的 CD8+细胞毒性 T 细胞（Tc）谱系，可能具有不同的抑制效应 CD4+T 细胞的能力。我们将纯化的人幼稚 CD8+T 细胞向 Tc0（培养基对照）、Tc1 和 Tc17 谱系分化。使用流式细胞术抑制试验，我们观察到 Tc0 和 Tc17 细胞具有相似的抑制能力。相比之下，Tc1 细胞对 CD4+T 细胞和分化的 Th0、Th1 和 Th17 细胞的抑制能力显著丧失。值得注意的是，Tc1 细胞在抑制 CD4 诱导的异种移植物抗宿主病（xGVHD）方面也不理想。在各种细胞因子组合下衍生的 Tc 亚型表明，含有 IL-12 的条件导致较少的抑制细胞表现出失调的细胞毒性脱颗粒。RNA 测序转录组分析表明炎症基因的差异调节和 GM-CSF 相关途径的富集。这些研究提供了对 T 细胞分化在 CD8 抑制生物学中的作用的深入了解，并可能揭示可治疗的靶向途径，以逆转免疫介导的疾病中的抑制缺陷。
