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 resting memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogen, but also have many properties in common with naïve cells, including the ability to migrate to lymph nodes and spleen, and their pluri-potency. Thus, memory cells embody features of both naïve and effector cells, fueling a long-standing debate centered on whether memory T cells develop from effector cells or directly from naïve cells1–4. To better define the developmental path of memory CD8 T cells we investigated changes in DNA methylation programming at naïve and effector genes in virus specific CD8 T cells during acute LCMV infection of mice. Methylation profiling of effector CD8 T cell subsets at day 4 and 8 after infection showed that, rather than retaining a naïve epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naïve-associated genes and became demethylated at loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase, Dnmt3a, at an early stage of effector differentiation strikingly reduced methylation of naïve-associated genes and resulted in faster re-expression of these naïve genes, accelerating memory cell development. Longitudinal phenotypic and epigenetic characterization of virus-specific memory-precursor CD8 T cells transferred into antigen-free mice revealed that their differentiation into memory cells was coupled to cell-division independent erasure of de novo methylation programs and re-expression of naïve-associated genes. These data provide evidence that epigenetic repression of naïve-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells supporting a differentiation model where memory T cells arise from a subset of fate-permissive effector T cells.

The metabolic spectrum of memory T cells

“…Further links between metabolism and epigenetic regulation of immune cells are beginning to emerge . Recent studies in mice and humans provide evidence that suggests memory T cells arise from effector T‐cell memory precursor pools and can retain an effector like epigenetic signature . This supports the concept that that memory T‐cell differentiation could be linked with epigenetic modifications at specific loci and that these cells are epigenetically poised to respond to secondary stimulation.…”

Active Maintenance of T Cell Memory in Acute and Chronic Viral Infection Depends on Continuous Expression of FOXO1

“…Finally, FOXO1 is dispensable during antigen-mediated expansion (or re-expansion) and acquisition of effector function (Hess Michelini et al, 2013), but it must be present in order to generate quiescent cells capable of re-expansion (serial activation and quiescence). This might occur through de-differentiation from effector T cells after the resolution of an infection (Youngblood et al, 2017). This would be in line with the hypothesis of FOXO1 preventing the deposition of the H3K27me3 at that stage on certain pro-memory genes in CD8 + T cells and thus facilitating the expression and perhaps the maintenance of an extended memory signature (Gray et al, 2017).…”

Eomesodermin driven IL-10 production in effector CD8+ T cells promotes a memory phenotype

“…The potential to acquire a memory phenotype is limited to 5-10% of antigen-specific CD8 + effector T cells (1, 2). This memory-precursor population is phenotypically distinct from terminally differentiated effector cells, as evidenced by distinct surface marker expression, transcription factor profiles and epigenetic signatures (1–6). …”