Hornung F, Scala G, Lenardo M J
Laboratory of Immunology and Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2000 Jun 15;164(12):6180-7. doi: 10.4049/jimmunol.164.12.6180.
Peripheral blood lymphocytes express CCR5, a chemokine receptor for immune cell migration and calcium signaling that serves as an important coreceptor for the HIV. After in vitro stimulation, CCR5 expression is dramatically increased on mature T lymphocytes, especially on the CD45RO+ memory subset. In this study, we report that TNF-alpha delays the surface expression of CCR5 on PBLs after activation and diminishes CCR5 irrespective of its initial level. Functional loss of CCR5 is reflected in a decreased capability of the treated cells to migrate and signal calcium after MIP-1beta stimulation. The effect is mediated via the p80 type II TNF receptor (TNFR2), which induces NF-kappaB among other factors, leading to an enhanced secretion of the chemokines macrophage-inflammatory protein-1alpha, macrophage-inflammatory protein-1beta, and RANTES. Expression of these chemokines directly down-regulates CCR5. These findings reveal a new regulatory mechanism utilized by activated peripheral T cells to modulate their chemotaxis and potentially other functions mediated by CCR5, including the infection of T lymphocytes by macrophage-tropic HIV strains.
外周血淋巴细胞表达CCR5，它是一种用于免疫细胞迁移和钙信号传导的趋化因子受体，是HIV的重要共受体。体外刺激后，成熟T淋巴细胞上CCR5的表达显著增加，尤其是在CD45RO +记忆亚群上。在本研究中，我们报告肿瘤坏死因子-α（TNF-α）会延迟激活后外周血淋巴细胞（PBLs）上CCR5的表面表达，并降低CCR5，无论其初始水平如何。CCR5的功能丧失表现为经处理的细胞在巨噬细胞炎性蛋白-1β（MIP-1β）刺激后迁移和钙信号传导能力下降。这种效应是通过p80 II型肿瘤坏死因子受体（TNFR2）介导的，TNFR2会诱导核因子-κB（NF-κB）等因子，导致趋化因子巨噬细胞炎性蛋白-1α、巨噬细胞炎性蛋白-1β和调节激活正常T细胞表达和分泌的因子（RANTES）的分泌增加。这些趋化因子的表达直接下调CCR5。这些发现揭示了活化的外周T细胞用于调节其趋化性以及潜在的其他由CCR5介导的功能（包括嗜巨噬细胞HIV毒株对T淋巴细胞的感染）的一种新的调节机制。
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