IL-27 promotes the expansion of self-renewing CD8+ T cells in persistent viral infection
IL-27 promotes the expansion of self-renewing CD8+ T cells in persistent viral infection
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DOI：
10.1084/jem.20190173
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发表时间：
2019-08-01
影响因子：
15.3
通讯作者：
Teijaro, John R.
中科院分区：
文献类型：
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作者：
Huang, Zhe;Zak, Jaroslav;Teijaro, John R.
慢性感染和癌症与在同源抗原存在的情况下T细胞反应受抑制有关。近期的研究发现了类记忆性CXCR5⁺ TCF1⁺ CD8⁺ T细胞，它们在持续性感染期间维持T细胞反应，并在抗PD1治疗时增殖。人们正在寻求扩增这些细胞的方法。我们发现，I型干扰素（IFN - I）受体的阻断以依赖IL - 27和STAT1的方式导致CXCR5⁺ CD8⁺ T细胞扩增。IFNAR1阻断促进了病毒特异性CD8⁺ T细胞的加速细胞分裂以及TCF1的保留。我们发现CD8⁺ T细胞内在的IL - 27信号传导保障了TCF1⁺⁺细胞维持增殖并避免终末分化或程序性细胞死亡的能力。从机制上讲，IL - 27赋予快速分裂的细胞IRF1，IRF1是一种以细胞内在方式维持分裂所必需的转录因子。这些发现表明，IL - 27对抗IFN - I，使效应分化与细胞分裂解偶联，并提示IL - 27信号传导可被利用来增加慢性感染和癌症中自我更新的T细胞。
Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5(+) TCF1(+) CD8(+) T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5(+) CD8(+) T cell expansion in an IL-27- and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8(+) T cells. We found that CD8(+) T cell-intrinsic IL-27 signaling safeguards the ability of TCF1(hi) cells to maintain proliferation and avoid terminal differentiation or programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings reveal that IL-27 opposes IFN-I to uncouple effector differentiation from cell division and suggest that IL-27 signaling could be exploited to augment self-renewing T cells in chronic infections and cancer.