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Origin and differentiation of human memory CD8 T cells after vaccination

Nature 552, 362–367 (21 December 2017) | Download Citation

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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.

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Acknowledgements

This work was supported by NIH grants U19AI057266 (R.A.), R01-AI43866-07 (M.H.), NIAID UM1 AI068618 (M.J.Mc.) and NIAID UM1 AI069481 (M.J.Mc.). The authors acknowledge technical support from R. Karaffa and S. Durham for cell sorting.

Author information

    • Shu Yang
    •  & Pramila Tata

    Present addresses: Xiangya School of Medicine, Central South University, Changsha, Hunan Province 410013, China (S.Y.); Syngene International, Bangalore, India (P.T.).

    • Mark Fitch
    •  & Srilatha Edupuganti

    These authors contributed equally to this work.

Affiliations

  1. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA

    • Rama S. Akondy
    • , Shu Yang
    • , Ben A. Youngblood
    • , Donald J. McGuire
    • , Megan M. McCausland
    • , Mark J. Mulligan
    •  & Rafi Ahmed

  2. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA

    • Rama S. Akondy
    • , Shu Yang
    • , Ben A. Youngblood
    • , Megan M. McCausland
    •  & Rafi Ahmed

  3. Department of Nutritional Sciences and Toxicology, UC Berkeley, Berkeley, California, USA

    • Mark Fitch
    •  & Marc Hellerstein

  4. Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, Georgia, USA

    • Srilatha Edupuganti
    • , Shashi Nagar
    •  & Mark J. Mulligan

  5. Department of Urology, Emory University School of Medicine, Atlanta, Georgia, USA

    • Haydn T. Kissick

  6. KineMed Inc., Emeryville California, USA

    • Kelvin W. Li
    •  & Marc Hellerstein

  7. St.Jude Children’s Research Hospital, Memphis, Tennessee, USA

    • Ben A. Youngblood
    •  & Hossam A. Abdelsamed

  8. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

    • Kristen W. Cohen
    •  & M. Juliana McElrath

  9. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Gabriela Alexe
    •  & W. Nicholas Haining

  10. Broad Institute of MIT and Harvard, Cambridge, Masschusetts 02142, USA

    • Gabriela Alexe
    •  & W. Nicholas Haining

  11. Strand Lifesciences, Bangalore, India

    • Satish Gupta
    •  & Pramila Tata

  12. Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA

    • David Zhang
    • , Bin Hu
    •  & Jorg J. Goronzy

  13. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA

    • William J. Greenleaf

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Contributions

R.A., M.H. and R.S.A. designed and analysed experiments. R.S.A., M.F., and S.Y. performed experiments with all other authors assisting with experiments and data analysis. H.T.K. and D.Z. analysed the genomics data. S.E., S.N. and M.J.Mu. directed the clinical part of human studies. M.J.Mc and K.W.C assisted with analysis of human CD8 T cells. R.S.A., K.W.L., H.T.K., R.A. and M.H. wrote the manuscript, with all authors providing feedback.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Marc Hellerstein or Rafi Ahmed.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended data figures

  1. 1.

    The dynamics of deuterium enrichment in body water.

  2. 2.

    Investigating the in vivo kinetics of YFV-specific CD8 T cells using heavy water labelling at a range of stages of the immune response to YFV-17D.

  3. 3.

    Transcriptional and epigenetic changes during effector and memory differentiation of YFV-specific CD8 T cells.

  4. 4.

    Pathways enriched in YFV-specific effector and memory CD8 T cells.

  5. 5.

    Naive and YFV memory CD8 T cell responses to homeostatic cytokines.

  6. 6.

    RNA-seq analysis of YFV tetramer-sorted effector and long-term memory CD8 T cells.

  7. 7.

    Comparing human YFV-specific effector and memory CD8 T cell signatures with mouse effector and memory CD8 T cells.

  8. 8.

    Analysis of open chromatin sites in YFV-specific effector and memory CD8 T cells using ATAC–seq.

  9. 9.

    Open chromatin sites near the TSSs of BCL2 and IL7R in YFV-specific effector and memory CD8 T cells.

  10. 10.

    Phenotypic comparison between YFV-specific long-term memory CD8 T cells and bulk stem-like memory (TSCM) CD8 T cell population.

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Tables

    This file contains supplementary tables 1-3. Supplementary Table1 - Raw data for deuterium labelling study 1. This table shows the cell division rate, cell growth raye and calculated death rate for each donor in the deuterium labelling study 1. Supplementary Table 2 - Comparing human YFV-specific effector and memory CD8 T cell signatures with mouse effector and memory CD8 T cells. The authors compared the RNA-seq data from YFV-tetramer+ CD8 T cells to published microarray data from mouse CD8 T cells. The authors performed gene set enrichment analysis (GSEA) to determine the degree of overlap of human YFV-specific CD8 T-cells with these mouse CD8 signatures. This table shows the p-value and FDR for each comparison. Supplementary Table 3- Donor Characteristics. The table shows the age, gender and race of the donors who participated in the heavy water labelling studies.

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DOI

https://doi.org/10.1038/nature24633

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