Origin and differentiation of human memory CD8 T cells after vaccination

• Authors: Rama Akondy, Emory University; Mark Fitch, University of California Berkeley; Srilatha Edupuganti, Emory University; Shu Yang, Emory University; Haydn Thomas Kissick, Emory University; Kelvin W. Li, KineMed Inc.; Ben A. Youngblood, Emory University; Hossam A. Abdelsamed, St.Jude Children’s Research Hospital; Donald J. McGuire, Emory University; Kristen W. Cohen, Fred Hutchinson Cancer Research Center; Gabriela Alexe, Harvard Medical School; Shashi Nagar, Emory University; Megan M. McCausland, Emory University; Satish Gupta, Strand Lifesciences; Pramila Tata, Strand Lifesciences; W. Nicholas Haining, Harvard Medical School; M. Juliana McElrath, Fred Hutchinson Cancer Research Center; David Zhang, Stanford University; Bin Hu, Stanford University; William J. Greenleaf, Stanford University; Jorg J. Goronzy, Stanford University; Mark Mulligan, Emory University; Marc Hellerstein, University of California Berkeley; Rafi Ahmed, Emory University
• Journal Title: Nature
• Volume: Volume 552, Number 7685
• Publisher: Nature Research (part of Springer Nature) | 2017-12-21, Pages 362-+
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/nature24633
• Subjects: Biology, Genetics; Biology, Microbiology; Health Sciences, Oncology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; VIRAL-INFECTION; LIFE-SPAN; EFFECTOR; TURNOVER; LYMPHOCYTES; EXHAUSTION

Abstract

The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days). Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells. This open chromatin profile at effector genes was maintained in memory CD8 T cells isolated even a decade after vaccination, indicating that these cells retain an epigenetic fingerprint of their effector history and remain poised to respond rapidly upon re-exposure to the pathogen.