Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation

Abstract

SUMMARY Metazoan sibling cells often diverge in activity and identity, suggesting links between growth signals and cell fate. We show that unequal transduction of nutrient-sensitive PI3K/AKT/mTOR signaling during cell division bifurcates transcriptional networks and fates of kindred cells. A sibling B lymphocyte with stronger signaling, indexed by FoxO1 inactivation and IRF4 induction, undergoes PI3K-driven Pax5 repression and plasma cell determination, while its sibling with weaker PI3K activity renews a memory or germinal center B cell fate. PI3K-driven effector T cell determination silences TCF1 in one sibling cell, while its PI3K-attenuated sibling self-renews in tandem. Prior to bifurcations achieving irreversible plasma or effector cell fate determination, asymmetric signaling during initial divisions specifies a more proliferative, differentiation-prone lymphocyte in tandem with a more quiescent memory cell sibling. By triggering cell division but transmitting unequal intensity between sibling cells, nutrient-sensitive signaling may be a frequent arbiter of cell fate bifurcations during development and repair.

Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification

“…Our data suggest that a key consequence of differential proteasome activity within CD8 + T cells that have undergone their first division in vivo is an alteration in their expression of Myc. These findings are consistent with recent reports demonstrating asymmetric PI3K signaling, Myc expression, and mTORC1 kinase activity following CD8 + T cell division (49,57,58). In the current study, we provide evidence supporting a role for Myc in influencing proteasome activitymediated effects on CD8 + T cell differentiation.…”

The PI3K Pathway in Human Disease

“…A later study showed that the CD8-high daughter cells retain higher mTORC1 activity (Figure 5), which drives c-Myc expression to promote glycolytic metabolism required for the effector CD8 T cell fate (Verbist et al, 2016). Bifurcation of PI3K/mTORC1 activity also contributes to differentiation fates in B cells and CD4 T cells (Lin et al, 2015; Nish et al, 2017; Pollizzi et al, 2016) (Figure 5). …”

Cytoskeletal control of B cell responses to antigens

“…During subsequent B cell proliferation, the polarity axis is maintained, resulting in asymmetric inheritance of the antigen processing compartment and other components into the daughter cells 128,130 . The function of the asymmetric division remains to be fully explored, but it is possible that it contributes to the diversity of B cell fates after activation, for example by the unequal capacity of the daughter cells to present antigen 128 , continue PI3K signalling 131 or regulate transcription by BCL6 130 . Through changes in polarity, the cytoskeleton may therefore regulate B cell differentiation into GC, plasma or memory cells.…”