Letter | Published:

Effector CD8 T cells dedifferentiate into long-lived memory cells

Nature volume 552, pages 404409 (21 December 2017) | Download Citation

Abstract

Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogens, but also have many properties in common with naive cells, including pluripotency and the ability to migrate to the lymph nodes and spleen. Thus, memory cells embody features of both naive and effector cells, fuelling a long-standing debate centred on whether memory T cells develop from effector cells or directly from naive cells1,2,3,4. Here we show that long-lived memory CD8 T cells are derived from a subset of effector T cells through a process of dedifferentiation. To assess the developmental origin of memory CD8 T cells, we investigated changes in DNA methylation programming at naive and effector cell-associated genes in virus-specific CD8 T cells during acute lymphocytic choriomeningitis virus infection in mice. Methylation profiling of terminal effector versus memory-precursor CD8 T cell subsets showed that, rather than retaining a naive epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naive-associated genes and became demethylated at the loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase Dnmt3a at an early stage of effector differentiation resulted in reduced methylation and faster re-expression of naive-associated genes, thereby accelerating the development of memory cells. Longitudinal phenotypic and epigenetic characterization of the memory-precursor effector subset of virus-specific CD8 T cells transferred into antigen-free mice revealed that differentiation to memory cells was coupled to erasure of de novo methylation programs and re-expression of naive-associated genes. Thus, epigenetic repression of naive-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells while key effector genes remain demethylated, demonstrating that memory T cells arise from a subset of fate-permissive effector T cells.

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Acknowledgements

We thank R. Karaffa and S. Durham at the Emory University School of Medicine Flow Cytometry Core Facility and R. Cross and G. Lennon in the St Jude Flow Cytometry Core Facility for FACS sorting. Whole-genome sequencing was performed by the St Jude Hartwell Sequencing facility. This work was supported by the National Institutes of Health (NIH) grant U19 AI117891 (to R.An.), R01AI030048 (to R.Ah.), U19AI057266 (to R.Ah.), R01AI114442(to B.Y.), and funds from American Lebanese Syrian Associated Charities (ALSAC) (to B.Y.).

Author information

Author notes

    • Xiaodong Cheng

    Present address: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Affiliations

  1. Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Ben Youngblood
    • , J. Scott Hale
    • , Eunseon Ahn
    • , Xiaojin Xu
    • , Andreas Wieland
    • , Koichi Araki
    • , Erin E. West
    • , Carl W. Davis
    • , Bogumila T. Konieczny
    •  & Rafi Ahmed
  2. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Ben Youngblood
    • , J. Scott Hale
    • , Eunseon Ahn
    • , Xiaojin Xu
    • , Andreas Wieland
    • , Koichi Araki
    • , Erin E. West
    • , Carl W. Davis
    • , Bogumila T. Konieczny
    •  & Rafi Ahmed
  3. Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Ben Youngblood
    • , Hazem E. Ghoneim
    •  & Pranay Dogra
  4. Department of Urology, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Haydn T. Kissick
  5. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA

    • Yiping Fan
  6. Department of Biology, Emory University, Atlanta, Georgia 30322, USA

    • Rustom Antia
  7. Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA

    • Xiaodong Cheng

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Contributions

B.Y. and J.S.H. designed experiments, collected, analysed data and interpreted results. H.T.K. analysed data and interpreted results. E.E.W., E.A., X.X. and A.W. collected data, analysed data and interpreted results. Y.F., K.A., X.C. and R.An. interpreted results. H.E.G., P.D., C.W.D. & B.T.K. collected data. R.Ah. designed experiments and supervised the study. All authors contributed to the preparation of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ben Youngblood or Rafi Ahmed.

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

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    Life Sciences Reporting Summary

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    Supplementary Table

    This file contains supplementary table 1 - Primers for Bisulfite Sequencing and Analysis of Dnmt3a Genomic Deletion.

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DOI

https://doi.org/10.1038/nature25144

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