A role for the chemokine RANTES in regulating CD8 T cell responses during chronic viral infection.
A role for the chemokine RANTES in regulating CD8 T cell responses during chronic viral infection.
复制标题
趋化因子在调节慢性病毒感染过程中调节CD8 T细胞反应的作用。
DOI：
10.1371/journal.ppat.1002098
复制
发表时间：
2011-07
期刊：
影响因子：
6.7
通讯作者：
Wherry EJ
中科院分区：
文献类型：
--
作者：
Crawford A;Angelosanto JM;Nadwodny KL;Blackburn SD;Wherry EJ
RANTES (CCL5) 是一种由许多造血和非造血细胞类型表达的趋化因子，在急性感染期间效应 T 细胞和记忆 T 细胞的归巢和迁移中发挥重要作用。 RANTES 受体 CCR5 是基于阻断病毒进入的抗 HIV 药物的主要靶点。然而，RANTES 或 RANTES 受体（包括 CCR5）的缺陷可能会损害动物模型中对急性感染的免疫力，并导致感染西尼罗河病毒 (WNV) 的人类患上更严重的疾病。相比之下，RANTES 通路在慢性感染期间调节 T 细胞反应和免疫的作用仍不清楚。在这项研究中，我们证明了 RANTES 在控制全身慢性 LCMV 感染中的关键作用。在 RANTES−/− 小鼠中，病毒特异性 CD8 T 细胞的细胞因子产生能力较差。这些 RANTES−/− CD8 T 细胞还表达更多的抑制性受体，这与更严重的衰竭相一致。此外，RANTES−/− 小鼠的 CD8 T 细胞的细胞毒性能力降低。因此，在没有 RANTES 的情况下，病毒载量更高。在缺乏 RANTES 的情况下，T 细胞的功能障碍与在缺乏 CD4 T 细胞帮助的情况下产生的 CD8 T 细胞反应一样严重。我们的结果表明，RANTES 在系统性慢性病毒感染期间维持 CD8 T 细胞反应中发挥着重要作用。趋化因子是吸引细胞并在协调免疫反应中发挥复杂作用的小蛋白质。 RANTES 就是这样一种趋化因子，可以吸引许多不同的细胞类型。 RANTES 受体 CCR5 也是 HIV 的辅助受体，阻断 RANTES∶CCR5 通路的药物已在临床上用于治疗 HIV 感染者。尽管 CCR5 在 HIV 感染期间很重要，但 RANTES 在其他慢性感染期间的作用仍然不明确。在这项研究中，我们发现 RANTES 的缺失限制了小鼠控制慢性 LCMV 感染的能力，导致更高的病毒载量和更严重的 T 细胞耗竭。我们的数据表明，在治疗 HIV 感染者时，应仔细考虑阻断 RANTES∶CCR5 通路对控制其他慢性感染的能力的影响。
RANTES (CCL5) is a chemokine expressed by many hematopoietic and non-hematopoietic cell types that plays an important role in homing and migration of effector and memory T cells during acute infections. The RANTES receptor, CCR5, is a major target of anti-HIV drugs based on blocking viral entry. However, defects in RANTES or RANTES receptors including CCR5 can compromise immunity to acute infections in animal models and lead to more severe disease in humans infected with west Nile virus (WNV). In contrast, the role of the RANTES pathway in regulating T cell responses and immunity during chronic infection remains unclear. In this study, we demonstrate a crucial role for RANTES in the control of systemic chronic LCMV infection. In RANTES−/− mice, virus-specific CD8 T cells had poor cytokine production. These RANTES−/− CD8 T cells also expressed higher amounts of inhibitory receptors consistent with more severe exhaustion. Moreover, the cytotoxic ability of CD8 T cells from RANTES−/− mice was reduced. Consequently, viral load was higher in the absence of RANTES. The dysfunction of T cells in the absence of RANTES was as severe as CD8 T cell responses generated in the absence of CD4 T cell help. Our results demonstrate an important role for RANTES in sustaining CD8 T cell responses during a systemic chronic viral infection. Chemokines are small proteins that attract cells and play complex roles in coordinating immune responses. RANTES is one such chemokine that attracts many different cell types. The receptor for RANTES, CCR5, is also a coreceptor for HIV and drugs blocking the RANTES∶CCR5 pathway are in clinical use to treat HIV-infected individuals. Despite the importance of CCR5 during HIV infection, the role of RANTES during other chronic infections remains poorly defined. In this study, we found that the absence of RANTES limited the ability of mice to control chronic LCMV infection resulting in higher viral loads and more severe T cell exhaustion. Our data suggest that the impact of blocking the RANTES∶CCR5 pathway on the ability to control other chronic infections should be given careful consideration when treating HIV-infected individuals.
登录
查看更多内容
影响因子：
15.9
作者：
Eberlein, Jens;Nguyen, Tom T.;Homann, Dirk
通讯作者：
Homann, Dirk
影响因子：
4.4
作者：
Grayson, Mitchell H.;Ramos, Madeleine S.;Holtzman, Michael J.
通讯作者：
Holtzman, Michael J.
影响因子：
32.4
作者：
Catalfamo, M;Karpova, T;Henkart, PA
通讯作者：
Henkart, PA
影响因子：
6.5
作者：
Esche, C;Stellato, C;Beck, LA
通讯作者：
Beck, LA
影响因子：
15.3
作者：
Dieu, M C;Vanbervliet, B;Vicari, A;Bridon, J M;Oldham, E;Ait-Yahia, S;Briere, F;Zlotnik, A;Lebecque, S;Caux, C
通讯作者：
Caux, C