Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells.
Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells.
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DOI：
10.1084/jem.20142237
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发表时间：
2015-06-29
期刊：
影响因子：
--
通讯作者：
Wherry EJ
中科院分区：
文献类型：
--
作者：
Odorizzi PM;Pauken KE;Paley MA;Sharpe A;Wherry EJ
使用PD-1缺陷小鼠和共过继转移方法，Odorizzi等人证明PD-1不是慢性LCMV感染中诱导CD 8 + T细胞耗竭（TEX）所必需的。PD-1的缺乏导致更多的细胞毒性，但终末分化的TEX，具有受损的长期耐久性。PD-1可以很好地保护TEX免受过度刺激、增殖和终末分化。程序性死亡-1（PD-1）作为慢性感染和癌症期间CD 8 + T细胞耗竭的关键调节因子受到了相当大的关注，因为该途径的阻断部分逆转了T细胞功能障碍。虽然PD-1通路在调节已建立的“耗竭”CD 8 + T细胞（TEX细胞）中至关重要，但目前尚不清楚PD-1是否直接导致T细胞耗竭。我们表明，PD-1是不需要的慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染的小鼠诱导衰竭。事实上，从感染开始，PD-1的基因缺失会使疲惫的某些方面更加严重。感染后第8天和第14天之间的增殖增加与随后的CD 8 + T细胞存活率降低和维持长期耗竭群体所必需的关键增殖层次的破坏有关。最终，PD-1的缺乏导致更多细胞毒性但终末分化的CD 8 + TEX细胞的积累。这些结果表明，在不存在PD-1的情况下可发生CD 8 + T细胞耗竭。他们还强调了PD-1在保护TEX细胞群免受过度刺激，过度增殖和终末分化方面的新作用。
Using PD-1–deficient mice and co-adoptive transfer approaches, Odorizzi et al. demonstrate that PD-1 is not required for the induction of CD8+ T cell exhaustion (TEX) in chronic LCMV infection. The absence of PD-1 leads to more cytotoxic, but terminally differentiated TEX, with compromised long-term durability. PD-1 may well serve to protect TEX from excessive overstimulation, proliferation, and terminal differentiation. Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8+ T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established “exhausted” CD8+ T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8+ T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8+ TEX cells. These results demonstrate that CD8+ T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.
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