Circulating CD8 T lymphocytes in human immunodeficiency virus-infected individuals have impaired function and downmodulate CD3 zeta, the signaling chain of the T-cell receptor complex.
Circulating CD8 T lymphocytes in human immunodeficiency virus-infected individuals have impaired function and downmodulate CD3 zeta, the signaling chain of the T-cell receptor complex.
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DOI：
10.1182/blood.v91.2.585.585_585_594
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发表时间：
1998-01
期刊：
影响因子：
20.3
通讯作者：
L. Trimble;J. Lieberman
中科院分区：
文献类型：
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作者：
L. Trimble;J. Lieberman
虽然没有获得性免疫缺陷综合征的人类免疫缺陷病毒（HIV）感染的受试者具有高频率的HIV特异性CD8 T淋巴细胞，但新分离的淋巴细胞往往缺乏可检测到的HIV特异性细胞毒性。然而，这种效应作用在过夜培养后变得很明显。为了研究t细胞功能障碍的原因，我们分析了t细胞中细胞溶解蛋白酶颗粒酶A和CD3 zeta的表达，CD3 zeta是t细胞受体复合物的信号传导成分。来自hiv感染供者的CD4和CD8 T细胞中含有颗粒酶A的比例增加，这与已知的激活T细胞频率增加相一致。在28名患有轻度至晚期免疫缺陷的hiv感染供者中，大量循环T细胞下调CD3 zeta（在健康供者中，表达CD3 zeta的T细胞比例为0.74 +/- 0.16 v 1.01 +/- 0.07, P < 0.00005）。CD3 zeta表达在CD8中比CD4 T细胞更严重下调，在感染早期降低，并与CD4计数下降和疾病分期相关。cd3zeta表达在培养6至16小时后以白细胞介素-2依赖性的方式增加，与病毒特异性细胞毒性的恢复一致。受损的T细胞受体信号可能有助于解释为什么HIV特异性细胞毒性T淋巴细胞不能控制HIV复制。
Although human immunodeficiency virus (HIV)-infected subjects without acquired immunodeficiency syndrome have a high frequency of HIV-specific CD8 T lymphocytes, freshly isolated lymphocytes frequently lack detectable HIV-specific cytotoxicity. However, this effector function becomes readily apparent after overnight culture. To investigate reasons for T-cell dysfunction, we analyzed T-cell expression of the cytolytic protease granzyme A and CD3 zeta, the signaling component of the T-cell receptor complex. An increased proportion of CD4 and CD8 T cells from HIV-infected donors contain granzyme A, consistent with the known increased frequency of activated T cells. In 28 HIV-infected donors with mild to advanced immunodeficiency, a substantial fraction of circulating T cells downmodulated CD3 zeta (fraction of T cells expressing CD3 zeta, 0.74 +/- 0.16 v 1.01 +/- 0.07 in healthy donors; P < .0000005). CD3 zeta expression is downregulated more severely in CD8 than CD4 T cells, decreases early in infection, and correlates with declining CD4 counts and disease stage. CD3 zeta expression increases over 6 to 16 hours of culture in an interleukin-2-dependent manner, coincident with restoration of viral-specific cytotoxicity. Impaired T-cell receptor signaling may help explain why HIV-specific cytotoxic T lymphocytes fail to control HIV replication.