Antigen-specific release of β-chemokines by anti-HIV-1 cytotoxic T lymphocytes
Antigen-specific release of β-chemokines by anti-HIV-1 cytotoxic T lymphocytes
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DOI：
10.1016/s0960-9822(98)70138-1
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发表时间：
1998-03-12
期刊：
影响因子：
9.2
通讯作者：
Phillips, RE
中科院分区：
文献类型：
--
作者：
Price, DA;Sewell, AK;Phillips, RE
人类免疫缺陷病毒（HIV）生物学的一个重大进展是发现β-趋化因子MIP-1 α（巨噬细胞炎性蛋白-1 α）、MIP-1 β（巨噬细胞炎症蛋白-1 β）和RANTES（在激活时调节，正常T细胞表达和分泌）抑制HIV-1进入CD 4（+）通过阻断CCR 5辅助受体和病毒包膜糖蛋白gp 120的V3结构域之间的关键相互作用[1，2]。CD 8（+）淋巴细胞是β-趋化因子的主要来源[3]，但对趋化因子释放的刺激尚未明确。在这里，我们已经表明，CD 8（+）细胞毒性T淋巴细胞（CTL）与HIV-1编码的人类白细胞抗原（HLA）I类限制性肽抗原的接合引起这些β-趋化因子的快速和特异性释放。这释放了细胞溶解活性，并且可以通过HLA I类限制性肽序列内天然存在的氨基酸变异来减弱。结合到适当的HLA I类分子但未能刺激CTL中的细胞溶解活性的表位变体也未能刺激趋化因子释放。我们得出结论，除了细胞溶解活性之外，抗原结合后通过T细胞受体（TCR）的信号传导还导致从CTL释放β-趋化因子，并且这两种反应都可以通过表位突变来消除。这些结果表明，HIV-1内的抗原变异可能不仅允许宿主细胞逃避裂解，而且可能通过未能激活β-趋化因子介导的HIV-1进入抑制而促进感染的传播。(C)Current Biology Ltd ISSN 0960-9822。
A major advance in understanding human immunodeficiency virus (HIV) biology was the discovery that the beta-chemokines MIP-1 alpha (macrophage inflammatory protein-1 alpha), MIP-1 beta (macrophage inflammatory protein-1 beta) and RANTES (regulated on activation, normal T-cell expressed and secreted) inhibit entry of HIV-1 into CD4(+) cells by blocking the critical interaction between the CCR5 coreceptor and the V3 domain of the viral envelope glycoprotein gp120 [1,2]. CD8(+) lymphocytes are a major source of beta-chemokines [3], but the stimulus for chemokine release has not been well defined. Here, we have shown that engagement of CD8(+) cytotoxic T lymphocytes (CTLs) with HIV-1-encoded human leukocyte antigen (HLA) class I-restricted peptide antigens caused rapid and specific release of these beta-chemokines. This release paralleled cytolytic activity and could be attenuated by naturally occurring amino acid variation within the HLA class I-restricted peptide sequence. Epitope variants that bound to appropriate HLA class I molecules but failed to stimulate cytolytic activity in CTLs also failed to stimulate chemokine release, We conclude that signalling through the T-cell receptor (TCR) following binding of antigen results in beta-chemokine release from CTLs in addition to cytolytic activity, and that both responses can be abolished by epitope mutation. These results suggest that antigenic variation within HIV-1 might not only allow the host cell to escape lysis, but might also contribute to the propagation of infection by failing to activate beta-chemokine-mediated inhibition of HIV-1 entry. (C) Current Biology Ltd ISSN 0960-9822.