Hadida F, Vieillard V, Autran B, Clark-Lewis I, Baggiolini M, Debré P
Laboratoire d'Immunologie Cellulaire, Unité de Recherche Associée, Centre National de la Recherche Scientifique 625, Bâtiment Centre d'Etudes et de Recherches en Virologie et Immunologie, Hôpital Pitié-Salpétrière, 75013 Paris, France.
J Exp Med. 1998 Aug 3;188(3):609-14. doi: 10.1084/jem.188.3.609.
CC chemokines produced by CD8(+) T cells are known to act as HIV-suppressive factors. We studied the possible role of these chemokines in HIV-1-specific killing of target cells. We found that the activity of cytotoxic T lymphocytes (CTLs) in CTL lines or freshly isolated peripheral blood mononuclear cells from HIV-1-infected individuals is markedly enhanced by RANTES (regulated on activation, normal T cell expressed and secreted) and virtually abolished by an antibody neutralizing RANTES or the RANTES receptor antagonist RANTES(9-68). Lysis was mediated by CD8(+) major histocompatibility complex class I-restricted T cells and was obtained with target cells expressing epitopes of the HIV-1LAI proteins Gag, Pol, Env, and Nef. The cytolytic activity observed in the presence or absence of added RANTES could be abolished by pretreatment of the CTLs with pertussis toxin, indicating that the effect is mediated by a G protein-coupled receptor. The chemokines monocyte chemotactic protein (MCP)-3, MCP-4, and eotaxin acted like RANTES, whereas macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, MCP-1, and stromal cell-derived factor 1 were inactive, suggesting a role for the eotaxin receptor, CCR3, and ruling out the involvement of CCR1, CCR2, CCR5, and CXCR4. CTL activity was abrogated by an antibody that blocks CCR3, further indicating that specific lysis is triggered via this chemokine receptor. These observations reveal a novel mechanism for the induction of HIV-1-specific cytotoxicity that depends on RANTES acting via CCR3.
已知CD8(+) T细胞产生的CC趋化因子可作为HIV抑制因子。我们研究了这些趋化因子在HIV-1特异性杀伤靶细胞中的可能作用。我们发现，来自HIV-1感染个体的CTL系或新鲜分离的外周血单核细胞中的细胞毒性T淋巴细胞（CTL）活性，被RANTES（受激活调节、正常T细胞表达和分泌）显著增强，而被中和RANTES的抗体或RANTES受体拮抗剂RANTES(9-68)几乎完全消除。细胞溶解由CD8(+)主要组织相容性复合体I类限制性T细胞介导，并且在表达HIV-1LAI蛋白Gag、Pol、Env和Nef表位的靶细胞中观察到。在添加或不添加RANTES的情况下观察到的细胞溶解活性，可通过用百日咳毒素预处理CTL而消除，表明该效应由G蛋白偶联受体介导。趋化因子单核细胞趋化蛋白（MCP）-3、MCP-4和嗜酸性粒细胞趋化因子的作用与RANTES相似，而巨噬细胞炎性蛋白（MIP）-1α、MIP-1β、MCP-1和基质细胞衍生因子1无活性，提示嗜酸性粒细胞趋化因子受体CCR3起作用，并排除了CCR1、CCR2、CCR5和CXCR4的参与。阻断CCR3的抗体可消除CTL活性，进一步表明特异性细胞溶解是通过该趋化因子受体触发的。这些观察结果揭示了一种诱导HIV-1特异性细胞毒性的新机制，该机制依赖于RANTES通过CCR3发挥作用。
