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

Abstract

SUMMARY Immunity following an acutely resolved infection or the long-term equipoise of chronic viral infections often depends on the maintenance of antigen-specific CD8+ T cells, 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+ T cells. We further establish FOXO1 regulation as a characteristic of human memory CD8+ T cells. Overall, we show that the molecular and functional longevity of a memory T cell population is actively maintained by the transcription factor FOXO1.

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

“…Indeed, studies using the inducible deletion of FOXO1 after resolution of viral infection suggest that memory cells require continuous FOXO1 activity to maintain their survival and transcriptional programming. 250,251 Furthermore, P2RX7 activates AMPK and restrains mTOR activation to promote memory CD8 + T-cell function, and transient P2RX7 blockade at the memory stage compromises the maintenance of memory CD8 + T cells. 252 Together, these results indicate that memory CD8 + T-cell fate is not an entirely default program but is an active process requiring regulatory networks, such as mTORC1 and mTORC2 signaling, to fix their lineage maturation.…”

Delineation of a molecularly distinct terminally differentiated memory CD8 T cell population

“…23) have been considered essential for the formation of TE or conventional TEM cells, whereas Eomes(24), Bcl6(25,26), Foxo1(27)(28)(29), Stat3(26), and Id3(22,30) have been linked to the differentiation of MP or TCM(3). Here, we demonstrated that optimal formation of the redefined TEM population was not impaired by diminished T-bet or Blimp1 expression.…”

“…We next examined the memory lineage-specifying roles of Bcl6 and Foxo1, transcription factors canonically recognized to support TCM formation relative to TEM (3,(25)(26)(27)(28)(29). As expected, loss of Bcl6 or or Foxo1 resulted in a loss of total memory P14 cells, including fewer TCM (blue bars) compared to control P14 cells ( Fig.…”

“…As our understanding of T cell states and fates has expanded, it has become evident that diverse intracellular and extracellular cues dictate CD8 T cell differentiation and homeostasis, ultimately through the dynamic activity of fate-specifying transcription factors (3,14). Canonical pro-effector transcription factors linked to the formation of TE cells and TEM include T-bet (11), Blimp1 (15,16), Zeb2 (17,18), Stat4 (19), and Id2 (20)(21)(22)(23), whereas pro-memory transcription factors required for optimal MP and TCM differentiation include Eomes (24), Bcl6 (25,26), Foxo1 (27)(28)(29), Stat3 (26), and Id3 (22,30). However, our ability to probe the molecular underpinnings of 4 TCM and TEM fates is limited by our capacity to accurately define and delineate these distinct memory populations.…”

Receptor signaling, transcriptional, and metabolic regulation of T cell exhaustion

“…Loss of FOXO1 in these infections led to the loss of TCF7+ memory like cells . 135 The TCF7 + CD8 memory precursors in vivo in chronic infections and cancer were recently found to represent two distinct subpopulations of exhausted T cells, the TCF7+ PD1+ and TCF7-PD1 + . The TCF7+ PD1+ were found to be with stem cell like properties, and the cells responsible for generating proliferative burst with anti-PD1 immunotherapy mediating tumor control as well as control of chronic viral infections.…”