Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor β1 deficiency
Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor β1 deficiency
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DOI：
10.4049/jimmunol.170.1.597
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发表时间：
2003-01-01
影响因子：
4.4
通讯作者：
Lewis, DB
中科院分区：
文献类型：
--
作者：
Cleary, AM;Tu, WW;Lewis, DB
IL-12产生或IL-12反应性的缺陷导致对非病毒细胞内生物感染的易感性，但导致这种易感性的免疫学机制仍然知之甚少。我们提出了一个病人的免疫学分析播散性肠炎沙门氏菌和纯合子剪接受体突变的IL-12Rbeta1链基因。这种突变导致PBMC上缺乏IL-12Rbeta1蛋白，T细胞无法与IL-12或IL-23特异性结合或产生干扰素-γ。记忆(CD45R0(高))CD4T细胞(CCR7(高))(可能是中央记忆细胞)的积累是正常的或随着年龄的增长而增加。患者和年龄匹配的对照组的中央记忆CD4T细胞在多克隆刺激后产生干扰素-γ的能力很低或检测不到。相比之下，患者的CCR7(阴性/无意义)CD45R0(高记忆性)CD45R0 T细胞(假定的效应记忆细胞)的数量显著减少，这些细胞与对照组细胞的不同之处在于，在多克隆刺激后产生干扰素-γ的能力最低。重要的是，与年龄匹配的对照组相比，患者PBMC产生的破伤风类毒素特异性干扰素-γ也显著减少，这表明通过IL-12Rbeta1链的信号通常对于体内积累具有Th1功能的人记忆CD4T细胞是必要的。这些结果也与一个模型一致，在该模型中，IL-12Rbeta1亚单位是中央记忆CD4T细胞转化为效应记忆细胞所必需的。
Defects in IL-12 production or IL-12 responsiveness result in a vulnerability to infection with non-viral intracellular organisms, but the immunological mechanisms responsible for this susceptibility remain poorly understood. We present an immunological analysis of a patient with disseminated Salmonella enteritidis and a homozygous splice acceptor mutation in the IL-12Rbeta1-chain gene. This mutation resulted in the absence of IL-12Rbeta1 protein on PBMC and an inability of T cells to specifically bind IL-12 or produce IFN-gamma in response to either IL-12 or IL-23. The accumulation of memory (CD45R0(high)) CD4 T cells that were CCR7(high) (putative central memory cells) was normal or increased for age. Central memory CD4 T cells of the patient and age-matched controls were similar in having a low to undetectable capacity to produce IFN-gamma after polyclonal stimulation. In contrast, the patient had a substantial decrease in the number of CCR7(neg/dull) CD45R0(high) memory CD4 T cells (putative effector memory cells), and these differed from control cells in having a minimal ability to produce IFN-gamma after polyclonal stimulation. Importantly, tetanus toxoid-specific IFN-gamma production by PBMC from the patient was also significantly reduced compared with that in age-matched controls, indicating that signaling via the IL-12Rbeta1-chain is generally necessary for the in vivo accumulation of human memory CD4 T cells with Th1 function. These results are also consistent with a model in which the IL-12Rbeta1 subunit is necessary for the conversion of central memory CD4 T cells into effector memory cells.