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Effector CD8 T cells dedifferentiate into long-lived memory cells
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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“These phenotypic changes correlate with increased expression of the master transcription factors TCF1 (encoded by Tcf7) or EOMES in absence of DNMT3A or TET2, respectively[164][165][166]183,187.”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [165]
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“In antigen-stimulated mouse CD8 + T cells and human chimeric antigen receptor (CAR) T cells, deficiency in DNMT3A or TET2 is associated with normal primary immune responses but enhanced secondary responses with increased memory precursor and central memory T cell differentiation 163-166,183,187 .”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [165]
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Metadata
- Authors
- Youngblood, B., Hale, J. S., Kissick, H. T., Ahn, E., Xu, X., Wieland, A., Araki, K., West, E. E., Ghoneim, H. E., Fan, Y., Dogra, P., Davis, C. W., Konieczny, B. T., Antia, R., Cheng, X., & Ahmed, R.
- Venue
- Nature
- Published
- 2017-12-13
- Volume
- 552
- Issue
- 7685
- Pages
- 404-409
- ISSN
- 0028-0836
- 1476-4687
- PMC
- PMC5965677
- Cited by
- 471
- References
- 39
- Language
- en
- Licence
- www.springer.com/tdm (tdm)
- www.springer.com/tdm (vor)
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