期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 42, 页码 E8865-E8874出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1618916114
关键词
immunology; host; pathogen; CD8(+) T cell; immune memory
资金
- NIH Grant [F32AI082933]
- UCSD Cancer Biology Fellowship
- Goldrath laboratory
- NIH [R01AI103440]
The factors and steps controlling postinfection CD8(+) T cell terminal effector versus memory differentiation are incompletely understood. Whereas we found that naive TCF7 (alias Tcf-1) expression is FOXO1 independent, early postinfection we report bimodal, FOXO1-dependent expression of the memory-essential transcription factor TCF7 in pathogen-specific CD8(+) T cells. We determined the early postinfection TCF7(high) population is marked by low TIM3 expression and bears memory signature hallmarks before the appearance of established memory precursor marker CD127 (IL-7R). These cells exhibit diminished TBET, GZMB, mTOR signaling, and cell cycle progression. Day 5 postinfection, TCF7high cells express higher memory-associated BCL2 and EOMES, as well as increased accumulation potential and capacity to differentiate into memory phenotype cells. TCF7 retroviral transduction opposes GZMB expression and the formation of KLRG1pos phenotype cells, demonstrating an active role for TCF7 in extinguishing the effector program and forestalling terminal differentiation. Past the peak of the cellular immune response, we report a gradient of FOXO1 and TCF7 expression, which functions to oppose TBET and orchestrate a continuum of effector-to-memory phenotypes.
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