CD4+ T help promotes influenza virus-specific CD8+ T cell memory by limiting metabolic dysfunction
CD4+ T help promotes influenza virus-specific CD8+ T cell memory by limiting metabolic dysfunction
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DOI：
10.1073/pnas.1808849116
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发表时间：
2019-03-05
影响因子：
11.1
通讯作者：
Turner, Stephen J.
中科院分区：
文献类型：
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作者：
Cullen, Jolie G.;McQuilten, Hayley A.;Turner, Stephen J.
人们继续对开发新的疫苗策略感兴趣，这些策略可以诱导对甲型流感病毒(IAV)等病原体建立最佳的CD8(+)细胞毒性T淋巴细胞(CTL)记忆，其中IAV特异性T细胞免疫的召回能够预防血清学上不同的IAV感染。虽然众所周知，最佳的CTL反应和记忆的建立需要CD4(+)T细胞的帮助，但CD4(+)T细胞何时以及如何帮助确定理想的记忆表型仍不清楚。我们评估了在存在或不存在同时存在的CD4(+)T细胞反应的情况下建立的IAV特异性CD8(+)T细胞记忆的质量。我们证明，在感染的初始启动阶段，CD4(+)T细胞的帮助似乎是维持IAV特异性CTL记忆所必需的，而“无帮助”的记忆CTL表现出内在的功能障碍。高通量RNA测序确定了不同的转录特征表征了有帮助和无帮助的IAV特异性记忆CTL表型，而无帮助的集合显示出更“疲惫的T细胞”的转录特征。此外，我们发现无助记忆CTL在各种能量途径上表现出缺陷，导致备用呼吸能力减弱，并在重新激活时参与糖酵解的能力减弱。因此，在初始启动时，CD4(+)T细胞帮助促进分子途径，通过引导对快速回忆记忆CD8(+)T细胞至关重要的代谢过程来限制疲劳。
There is continued interest in developing novel vaccine strategies that induce establish optimal CD8(+) cytotoxic T lymphocyte (CTL) memory for pathogens like the influenza A viruses (IAVs), where the recall of IAV-specific T cell immunity is able to protect against serologically distinct IAV infection. While it is well established that CD4(+) T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4(+) T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8(+) T cell memory established in the presence or absence of a concurrent CD4(+) T cell response. We demonstrate that CD4(+) T cell help appears to be required at the initial priming phase of infection for the maintenance of IAV-specific CTL memory, with "unhelped" memory CTL exhibiting intrinsic dysfunction. High-throughput RNA-sequencing established that distinct transcriptional signatures characterize the helped vs. unhelped IAV-specific memory CTL phenotype, with the unhelped set showing a more "exhausted T cell" transcriptional profile. Moreover, we identify that unhelped memory CTLs exhibit defects in a variety of energetic pathways, leading to diminished spare respiratory capacity and diminished capacity to engage glycolysis upon reactivation. Hence, CD4(+) T help at the time of initial priming promotes molecular pathways that limit exhaustion by channeling metabolic processes essential for the rapid recall of memory CD8(+) T cells.