IL-12-Induced Immune Suppressive Deficit During CD8+ T-Cell Differentiation.
IL-12-Induced Immune Suppressive Deficit During CD8+ T-Cell Differentiation.
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DOI：
10.3389/fimmu.2020.568630
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发表时间：
2020
影响因子：
7.3
通讯作者：
Karandikar NJ
中科院分区：
文献类型：
--
作者：
Renavikar PS;Sinha S;Brate AA;Borcherding N;Crawford MP;Steward-Tharp SM;Karandikar NJ
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细胞在免疫抑制能力方面明显不足。我们假设，由初始T细胞分化过程中的细胞因子环境所决定的不同的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。我们在体外将纯化的人初始CD8 + T细胞分别向Tc0（培养基对照）、Tc1和Tc17谱系分化。通过体外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细胞对体外的CD4 + T细胞以及体外分化的Th0、Th1和Th17细胞的抑制能力显著丧失。值得注意的是，Tc1细胞在体内抑制CD4诱导的急性异种移植物抗宿主病（xGVHD）方面也效果欠佳。在各种细胞因子组合下分化得到的Tc亚型显示，含IL - 12的条件会导致抑制能力较弱的细胞出现细胞毒性脱颗粒失调。RNA测序转录组分析表明炎症基因的调控存在差异，并且在粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）相关通路中富集。这些研究深入了解了T细胞分化在CD8抑制生物学中的作用，并可能揭示在免疫介导疾病期间可作为治疗靶点的通路，以逆转抑制缺陷。
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 in vitro toward Tc0 (media control), Tc1 and Tc17 lineages. Using in vitro 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 ex vivo CD4+ T-cells and in vitro-differentiated Th0, Th1 and Th17 cells. Of note, Tc1 cells were also suboptimal in suppressing CD4-induced acute xenogeneic graft versus host disease (xGVHD) in vivo. 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.
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DOI：
10.1084/jem.20021910
发表时间：
2003-05-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Mescher MF
影响因子：
30.5
作者：
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通讯作者：
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影响因子：
15.9
作者：
BALASHOV, KE;KHOURY, SJ;WEINER, HL
通讯作者：
WEINER, HL
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DOI：
10.1016/j.jaci.2017.10.040
发表时间：
2018-09
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
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影响因子：
5.4
作者：
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通讯作者：
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