Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, Hamilton, MT, 59840, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Nat Commun. 2019 Feb 15;10(1):794. doi: 10.1038/s41467-019-08637-9.
Prolonged exposure of CD8 T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8 T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα CD8 T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8 T cell-killing in vivo. SIRPα CD8 T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8 T cells during chronic infection expands the cytotoxic subset of SIRPα CD8 T cells.
CD8 T 细胞在抗原刺激下持续暴露，如在慢性病毒感染中，会导致一种功能减弱的状态，称为衰竭。我们现在证明，即使在衰竭过程中，仍有一部分具有功能的 CD8 T 细胞，其特征是表面表达 SIRPα，这是一种以前未在淋巴细胞上报告过的蛋白。在 SIRPα+CD8 T 细胞上，共抑制受体的表达被共刺激受体的表达所平衡，只有 SIRPα+细胞才会积极增殖、转录 IFNγ并表现出细胞毒性活性。此外，表达 SIRPα配体 CD47 的靶细胞在体内更容易被 CD8 T 细胞杀伤。在感染 Friend 逆转录病毒、LCMV Clone 13 的小鼠和慢性 HCV 感染患者中都可以观察到 SIRPα+CD8 T 细胞。此外，在慢性感染期间，通过阻断 PD-L1 来重振 CD8 T 细胞会扩增 SIRPα+CD8 T 细胞的细胞毒性亚群。
