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

Daniel T Utzschneider,Arnaud Delpoux,Dominik Wieland,Xin Huang,Chen-Yen Lai,Maike Hofmann,Robert Thimme,Stephen M Hedrick

doi:10.1016/j.celrep.2018.03.020

Daniel T Utzschneider, Arnaud Delpoux + Show 6 more

Open Access

https://doi.org/10.1016/j.celrep.2018.03.020

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Abstract

Immunity following an acutely resolved infection or the long-term equipoise of chronic viral infections often depends on the maintenance of antigen-specific CD8+ Tcells, yet the ongoing transcriptional requirements of these cells remain unclear. We show that active and continuous programming by FOXO1 is required for the functional maintenance of a memory population. Upon Foxo1 deletion following resolution of an infection, memory cells rapidly lost their characteristic gene expression, gradually declined in number, and were impaired in self-renewal. This was extended to chronic infections, as a loss of FOXO1 during a persistent viral infection led to a rapid decline of the TCF7 (a.k.a. TCF1)-expressing memory-like subset of CD8+ Tcells. We further establish FOXO1 regulation as a characteristic of human memory CD8+ Tcells. Overall, we show that the molecular and functional longevity of a memory Tcell population is actively maintained by the transcription factor FOXO1.

Highlights

Functional immune memory governed by CD8+ T cells is indispensable for resistance to bacterial and viral re-infection
We were interested in determining the role of continuous FOXO1 expression in memory CD8+ T cells and how this impacts cardinal aspects of a memory T cell population including longevity and the ability to mount a recall response
C57BL/6 mice grafted with similar numbers (5 3 104) of WT- and iFx1f/f-P14 cells were infected with lymphocytic choriomeningitis virus (LCMV) Arm. 4 weeks post-infection, KLRG1À WT- and KLRG1À iFx1f/f-P14 were fluorescence-activated cell sorting (FACS) purified from spleen and lymph nodes, labeled with CellTrace violet (CTV), and co-transferred into naive C57BL/6 hosts, which were 1 day later treated with TAM. (J) Purification control of transferred KLRG1À WT- and KLRG1À iFx1f/f-P14. (K–P) Splenocytes were stained for expression of killer cell lectin-like receptor G1 (KLRG1) and CD62L. (K–M) Representative FACS plots illustrating the fraction of undivided KLRG1-expressing KLRG1À WT- and KLRG1À iFx1À/À-P14 (K) as well as the calculated fraction (L) and absolute numbers (M) for all mice. (N–P) Fraction (N and O) and absolute numbers (P) of undivided CD62LÀ WT- and CD62LÀ iFx1À/À-P14

Summary

Introduction

Functional immune memory governed by CD8+ T cells is indispensable for resistance to bacterial and viral re-infection. The ability to provide such protection relies on the longevity of a memory population and its ability to mount a robust recall response when re-exposed to antigen derived from the same pathogen. Along with the unusual property of self-renewal, memory CD8+ T cells display the unique ability to serially transit through phases of activation, growth, and proliferation followed by quiescence. In essence, they exhibit characteristics of multipotent stem cells that simultaneously self-renew and produce progenitors of terminally differentiated cells (Gattinoni et al, 2017; Fearon et al, 2001). The ongoing transcriptional requirements for the homeostasis of memory cells through these phases are still under investigation

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