Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
Front Immunol. 2020 Jan 8;10:3005. doi: 10.3389/fimmu.2019.03005. eCollection 2019.
Effective CD8 T-cell responses play an important role in determining the course of SIV/HIV viral infection. Here we identified a unique population of dysfunctional CD8 T-cells in lymphoid tissues and bronchoalveolar lavage (BAL) of rhesus macaques with chronic SIV infection characterized by co-expression of CD6 and PD-1. The frequency of CD6 and PD-1 co-expressing CD8 T-cells was significantly increased in lymphoid tissues and BAL during chronic SIV infection compared to pre-infection levels. These CD6PD-1CD8 T-cells displayed impaired proliferation, cytokine secretion and cytotoxicity compared to their CD6PD-1CD8 T cell counterparts. The frequency of CD8PD-1 and CD8CD6PD-1 T-cells in the lymph node and bone marrow did not correlate with SIV viral load, whereas the frequency of CD8CD6PD-1 T-cells positively correlated with SIV viral load in these tissues highlighting the contribution of CD6 to disease progression. CD6PD-1CD8 T-cells expressed elevated levels of SHP2 phosphatase compared to CD6PD-1CD8 T-cells providing a potential mechanism by which CD6 may induce T-cell dysfunction during chronic SIV infection. Combined targeting of CD6 and PD-1 effectively revived the CD8 T-cell proliferative response suggesting a strategy for potential therapeutic benefit.
有效的 CD8 T 细胞应答在决定 SIV/HIV 病毒感染过程中起着重要作用。在这里，我们在慢性 SIV 感染的恒河猴淋巴组织和支气管肺泡灌洗液（BAL）中鉴定到一群具有独特功能障碍的 CD8 T 细胞，其特征是共表达 CD6 和 PD-1。与感染前水平相比，在慢性 SIV 感染期间，淋巴组织和 BAL 中 CD6 和 PD-1 共表达的 CD8 T 细胞的频率显著增加。与 CD6PD-1CD8 T 细胞相比，这些 CD6PD-1CD8 T 细胞的增殖、细胞因子分泌和细胞毒性受损。淋巴结和骨髓中 CD8PD-1 和 CD8CD6PD-1 T 细胞的频率与 SIV 病毒载量无关，而这些组织中 CD8CD6PD-1 T 细胞的频率与 SIV 病毒载量呈正相关，突出了 CD6 对疾病进展的贡献。与 CD6PD-1CD8 T 细胞相比，CD6PD-1CD8 T 细胞表达更高水平的 SHP2 磷酸酶，为 CD6 在慢性 SIV 感染期间诱导 T 细胞功能障碍提供了一种潜在机制。CD6 和 PD-1 的联合靶向有效地恢复了 CD8 T 细胞的增殖反应，提示这是一种潜在的治疗益处策略。
