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Author Notes:

Correspondence and requests for materials should be addressed to Dr. Rafi Ahmed or Dr. Ben Youngblood. Department of Microbiology and Immunology, Emory University, 1510 Clifton Road, Atlanta, GA 30322 rahmed@emory.edu or Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 benjamin.youngblood@stjude.org.

BY & JSH designed experiments, collected data, analyzed and interpreted results.

HTK analyzed and interpreted results.

EEW, EA, XX, & AW collected data, analyzed and interpreted results.

YF, KA, XC, & RA interpreted results.

HG, PD, CWD & BTK collected data.

RA designed experiments and supervised the study.

All authors contributed in the preparation of the manuscript.

We thank R. Karaffa and S. Durham at the Emory University School of Medicine Flow Cytometry Core Facility Richard Cross and Greig Lennon in the St Jude Flow Cytometry Core Facility for FACS sorting.

Whole-genome sequencing was performed by the St Jude Hartwell Sequencing facility.

The authors report no competing financial interests.

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Research Funding:

This work was supported by the National Institutes of Health (NIH) grant 1 P01 AI080192-01 (to R.A.), grant 2 R37 AI30048-17 (to R.A.), grant AHMED05GCGH0 (to R.A.), and funds from American Lebanese Syrian Associated Charities (ALSAC) (to B.A.Y.).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MOUSE L-SELECTIN
  • TRANSCRIPTION FACTOR
  • LYMPHOCYTE DIVISION
  • VIRAL PERSISTENCE
  • DNA METHYLATION
  • DIFFERENTIATION
  • ANTIGEN
  • FATES
  • EXPRESSION
  • INFECTION

Effector CD8 T cells dedifferentiate into long-lived memory cells

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Journal Title:

Nature

Volume:

Volume 552, Number 7685

Publisher:

, Pages 404-+

Type of Work:

Article | Post-print: After Peer Review

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 cells. 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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© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

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