Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders.
Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders.
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DOI：
10.1084/jem.20140039
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发表时间：
2014-09-22
期刊：
影响因子：
--
通讯作者：
Pantaleo G
中科院分区：
文献类型：
--
作者：
Perreau M;Vigano S;Bellanger F;Pellaton C;Buss G;Comte D;Roger T;Lacabaratz C;Bart PA;Levy Y;Pantaleo G
常见变异型免疫缺陷（CVID）的特点是血液中抗体水平异常低，免疫细胞功能失调，称为CD 4 + T细胞。Perreau等人现在证明，由于正常肠道细菌不断泄漏到血液中，这些患者的抗细菌CD 4 + T细胞处于衰竭状态，这可能是由于抗体水平不足。在本研究中，我们研究了常见变异型免疫缺陷（CVID）患者的CD 4 T细胞的功能概况，包括细胞因子的产生和对细菌和病毒衍生抗原的增殖反应。我们发现，CD 4 T细胞的功能受损，包括增殖和产生IFN-γ和IL-2的能力降低，仅限于细菌特异性而非病毒特异性CD 4 T细胞。CVID患者血浆内毒素水平较高，提示细菌移位可能导致CD 4 T细胞功能障碍。值得注意的是，内毒素血症与CD 4 T细胞上程序性死亡1（PD-1）的显著较高表达相关。PD-1-PD-L1/2轴的体外阻断恢复了CD 4 T细胞增殖能力，从而表明PD-1信号传导负调节CD 4 T细胞功能。最后，我们发现静脉注射免疫球蛋白G（IVIG）治疗显著降低了内毒素血症和PD-1+ CD 4 T细胞的百分比，并恢复了细菌特异性CD 4 T细胞细胞因子的产生和增殖。总之，本研究表明，CVID患者中观察到的CD 4 T细胞耗竭和功能障碍与细菌易位相关，IVIG治疗可解决细菌易位并恢复CD 4 T细胞功能。
Common variable immunodeficiency (CVID) is characterized by abnormally low levels of antibodies in the blood and dysfunctional immune cells called CD4+ T cells. Perreau et al. now show evidence that bacteria-fighting CD4+ T cells in these patients are in a state of exhaustion due to a constant leakage of normal gut bacteria into the bloodstream, possibly due to insufficient antibody levels. In the present study, we have investigated the functional profile of CD4 T cells from patients with common variable immunodeficiency (CVID), including production of cytokines and proliferation in response to bacteria and virus-derived antigens. We show that the functional impairment of CD4 T cells, including the reduced capacity to proliferate and to produce IFN-γ and IL-2, was restricted to bacteria-specific and not virus-specific CD4 T cells. High levels of endotoxins were found in the plasma of patients with CVID, suggesting that CD4 T cell dysfunction might be caused by bacterial translocation. Of note, endotoxemia was associated with significantly higher expression of programmed death 1 (PD-1) on CD4 T cells. The blockade of the PD-1–PD-L1/2 axis in vitro restored CD4 T cell proliferation capacity, thus indicating that PD-1 signaling negatively regulates CD4 T cell functions. Finally, we showed that intravenous immunoglobulin G (IVIG) treatment significantly reduced endotoxemia and the percentage of PD-1+ CD4 T cells, and restored bacteria-specific CD4 T cell cytokine production and proliferation. In conclusion, the present study demonstrates that the CD4 T cell exhaustion and functional impairment observed in CVID patients is associated with bacterial translocation and that IVIG treatment resolves bacterial translocation and restores CD4 T cell functions.
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