A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation
A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation
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DOI：
10.1084/jem.20182015
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发表时间：
2019-06-01
影响因子：
15.3
通讯作者：
Hsieh, Elena W. Y.
中科院分区：
文献类型：
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作者：
Fernandez, Isabel Z.;Baxter, Ryan M.;Hsieh, Elena W. Y.
白细胞介素-2（IL-2）的多效性作用对于调节免疫应答和维持免疫耐受是必不可少的。IL-2受体（IL-2 R）由IL-2 R α、IL-2 R β和IL-2 R γ亚基组成，其中IL-2 R α和IL-2 R γ及其下游信号传导效应物的缺陷导致已知的原发性免疫缺陷病症。在这里，我们报告了第一个人类IL-2 R β缺陷，发生在两个婴儿兄弟姐妹与纯合子IL 2 RB突变的WSXWS基序，表现为多系统自身免疫和CMV感染的易感性。亚型突变导致IL-2 R β表面表达减少和IL-2/15信号转导失调，预期调节性T细胞减少。然而，与缺乏NK细胞的IL-2 R β（-/-）动物模型相反，这些同胞显示NK细胞的扩增，特别是CD 56（亮）亚群，并且缺乏终末分化的NK细胞。因此，早发性自身免疫和免疫缺陷与T和NK细胞中IL-2 R β表达和信号传导改变引起的功能缺陷有关。
The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2R alpha, IL-2R beta, and IL-2R gamma subunits, with defects in IL-2R alpha and IL-2R gamma and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2R beta, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2R beta surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2R beta(-/-) animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56(bright) subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2R beta expression and signaling in T and NK cells.