Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8(+) T-cell memory formation and function.
Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8(+) T-cell memory formation and function.
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DOI：
10.1016/j.jaci.2013.05.029
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发表时间：
2013-08
期刊：
影响因子：
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通讯作者：
Deenick EK
中科院分区：
文献类型：
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作者：
Ives ML;Ma CS;Palendira U;Chan A;Bustamante J;Boisson-Dupuis S;Arkwright PD;Engelhard D;Averbuch D;Magdorf K;Roesler J;Peake J;Wong M;Adelstein S;Choo S;Smart JM;French MA;Fulcher DA;Cook MC;Picard C;Durandy A;Tsumura M;Kobayashi M;Uzel G;Casanova JL;Tangye SG;Deenick EK
CD 8 + T细胞控制感染和介导抗肿瘤免疫的能力需要效应细胞和记忆细胞的发育和存活。IL-21已成为感染性疾病小鼠模型中CD 8 + T细胞效应子功能和记忆发育的有效诱导剂。然而，IL-21和相关信号通路在人类保护性CD 8 + T细胞免疫中的作用尚不清楚。确定哪些信号通路介导IL-21对人CD 8 + T细胞的作用，以及这些通路中的缺陷是否有助于IL-21信号级联组分突变引起的原发性免疫缺陷的疾病发病机制。由单基因突变引起的人类原发性免疫缺陷提供了一个独特的机会来评估特定分子在调节人类淋巴细胞功能中的需求。来自在STAT 1、STAT 3或IL 21 R中具有功能丧失突变的患者的淋巴细胞用于评估这些基因在体内和体外人CD 8 + T细胞分化中的各自作用。STAT 3和IL-21 R的突变，而不是STAT 1，导致体内多种记忆CD 8 + T细胞亚群的减少，表明STAT 3信号传导-可能在IL-21 R的下游-调节记忆细胞库。此外，STAT 3对于诱导IL-21刺激的幼稚CD 8 + T细胞中的溶解机制是重要的。然而，该缺陷通过TCR接合而被克服。IL-21 R/STAT 3通路是人CD 8 + T细胞行为的许多方面所必需的，但在某些情况下可以通过其他信号进行补偿。这有助于解释在STAT 3和IL-21 R缺陷个体中观察到的对病毒性疾病的相对轻度易感性。
The capacity of CD8+ T cells to control infections and mediate anti-tumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8+ T cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8+ T cell immunity in humans is unknown. To determine which signaling pathways mediate the effects of IL-21 on human CD8+ T cells and whether defects in these pathways contribute to disease pathogenesis in primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade. Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in STAT1, STAT3 or IL21R were used to assess the respective roles of these genes in human CD8+ T cell differentiation in vivo and in vitro. Mutations in STAT3 and IL21R, but not STAT1, lead to a decrease in multiple memory CD8+ T cell subsets in vivo, indicating that STAT3 signaling – possibly downstream of IL-21R - regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naïve CD8+ T cells. However, this defect was overcome by TCR engagement. The IL-21R/STAT3 pathway is required for many aspects of human CD8+ T cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3 and IL-21R-deficient individuals.