期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 10, 页码 4481-4488出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1808849116
关键词
CD8(+) T cell; immunological memory; CD4 T cell; influenza; metabolism
资金
- National Health and Medical Research Council of Australia [5671222, APP1003131]
- Australian Research Council Future Fellowship
- National Health and Medical Research Council Principal Research fellowship
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.
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