Homeostatic Cytokines Drive Epigenetic Reprogramming of Activated T Cells into a "Naive-Memory" Phenotype.

Guido Frumento,Frederick E Chen,Andrea White,Stephen Kissane,Wayne Croft,Kriti Verma,Paul Moss,Graham Anderson,Zsuzsanna Nagy,Jianmin Zuo

doi:10.1016/j.isci.2020.100989

Abstract

SummaryPrimary stimulation of T cells is believed to trigger unidirectional differentiation from naive to effector and memory subsets. Here we demonstrate that IL-7 can drive the phenotypic reversion of recently differentiated human central and effector memory CD8+ T cells into a naive-like phenotype.These “naive-revertant” cells display a phenotype similar to that of previously reported stem cell memory populations and undergo rapid differentiation and functional response following secondary challenge. The chromatin landscape of reverted cells undergoes substantial epigenetic reorganization with increased accessibility for cytokine-induced mediators such as STAT and closure of BATF-dependent sites that drive terminal differentiation. Phenotypic reversion may at least partly explain the generation of “stem cell memory” CD8+ T cells and reveals cells within the phenotypically naive CD8+ T cell pool that are epigenetically primed for secondary stimulation. This information provides insight into mechanisms that support maintenance of T cell memory and may guide therapeutic manipulation of T cell differentiation.

Highlights

The development of T cell memory is essential for long-term health but it remains uncertain how this population is maintained over the many decades of human lifespan
We demonstrate that IL-7 can drive the phenotypic reversion of recently differentiated human central and effector memory CD8+ T cells into a naive-like phenotype
Phenotypic reversion may at least partly explain the generation of ‘‘stem cell memory’’ CD8+ T cells and reveals cells within the phenotypically naive CD8+ T cell pool that are epigenetically primed for secondary stimulation

Summary

Introduction

The development of T cell memory is essential for long-term health but it remains uncertain how this population is maintained over the many decades of human lifespan. T cells gradually acquire increasing effector function but this is associated with a progressive reduction in the capacity for differentiation and self-renewal, i.e., ‘‘stemness.’’ In settings of persistent antigenic stimulations T cells may progressively lose effector functions and proliferative capacity such that they eventually become exhausted. ‘‘T-memory stem cells’’ (TSCM), which display enhanced capacity for self-renewal and multipotent proliferative potential (Gattinoni et al, 2011), are believed to be minimally differentiated and located between TN and TCM in the differentiation pathway (Gattinoni et al, 2017). ‘‘Memory T cells with naive phenotype’’ (TMNP) exhibit broad polyfunctional capability (Pulko et al, 2016) and are thought to be functionally imprinted at an early stage of differentiation between CD8+ TN and TCM subsets. CD8+ TSCM can be produced in vitro by activating TN cells in the presence of interleukin (IL)-7, IL-21, and the glycogen synthase-3b inhibitor TWS119 9 (Sabatino et al, 2016), the physiological mechanisms leading to the generation of both these cells and TMNP are largely unknown

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Discussion

Conclusion