Familial NK cell deficiency associated with impaired IL-2-and IL-15-dependent survival of lymphocytes
Familial NK cell deficiency associated with impaired IL-2-and IL-15-dependent survival of lymphocytes
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DOI：
10.4049/jimmunol.177.12.8835
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发表时间：
2006-12-15
影响因子：
4.4
通讯作者：
Casanova, Jean-Laurent
中科院分区：
文献类型：
--
作者：
Eidenschenk, Celine;Jouanguy, Enunanuelle;Casanova, Jean-Laurent
我们之前报道了两个兄弟姐妹的临床表型，他们患有一种新型的遗传性发育和免疫缺陷综合征，包括严重的宫内生长迟缓和特定淋巴细胞谱系的发育受损，包括短暂的CD8 α - β T淋巴细胞减少症和持续的血液NK细胞缺乏。我们在这里描述了一种可能的潜在致病机制的阐明，在存活的儿童中，新鲜和疱疹病毒转化的猴猴T细胞的细胞表型受损。显然，NK细胞不能被研究。然而，外周血T淋巴细胞在体外表现出过度的凋亡。此外，经IL-2和IL-15治疗后，体外培养的CD4和CD8 α - β T细胞母细胞以及体外培养的疱疹病毒猴胚转化T细胞的存活率较低，但并非为零。相反，fas介导的激活诱导的细胞死亡没有增强，表明细胞因子剥夺介导的细胞凋亡选择性过量。与已知的IL-2和IL-15在小鼠模型中NK和CD8 T细胞发育中的作用一致，这些数据表明，对IL-2和IL-15的生存反应受损，但并未消除，这是体内记录的NK细胞持续缺乏和短暂性CD8 α - β T淋巴细胞减少的原因。细胞因子介导的淋巴细胞存活受损可能是人类遗传和选择性NK缺乏这种新形式的致病机制。
We previously reported the clinical phenotype of two siblings with a novel inherited developmental and immunodeficiency syndrome consisting of severe intrauterine growth retardation and the impaired development of specific lymphoid lineages, including transient CD8 alpha beta T lymphopenia and a persistent lack of blood NK cells. We describe here the elucidation of a plausible underlying pathogenic mechanism, with a cellular phenotype of impaired survival of both fresh and herpesvirus saimiri-transformed T cells, in the surviving child. Clearly, NK cells could not be studied. However, peripheral blood T lymphocytes displayed excessive apoptosis ex vivo. Moreover, the survival rates of CD4 and CD8 alpha beta T cell blasts generated in vitro, and herpesvirus saimiri-transformed T cells cultured in vitro, were low, but not nil, following treatment with IL-2 and IL-15. In contrast, Fas-mediated activation-induced cell death was not enhanced, indicating a selective excess of cytokine deprivation-mediated apoptosis. In keeping with the known roles of IL-2 and IL-15 in the development of NK and CD8 T cells in the mouse model, these data suggest that an impaired, but not abolished, survival response to IL-2 and IL-15 accounts for the persistent lack of NK cells and the transient CD8 alpha beta T lymphopenia documented in vivo. Impaired cytokine-mediated lymphocyte survival is likely to be the pathogenic mechanism underlying this novel form of inherited and selective NK deficiency in humans.