Asymmetric PI3K Activity in Lymphocytes Organized by a PI3K-Mediated Polarity Pathway

Abstract

SUMMARYUnequal transmission of nutritive signaling during cell division establishes fate disparity between sibling lymphocytes, but how asymmetric signaling becomes organized is not understood. We show that receptor-associated class I phosphatidylinositol 3-kinase (PI3K) signaling activity, indexed by phosphatidylinositol (3,4,5)-trisphosphate (PIP3) staining, is spatially restricted to the microtubule-organizing center and subsequently to one pole of the mitotic spindle in activated T and B lymphocytes. Asymmetric PI3K activity co-localizes with polarization of antigen receptor components implicated in class I PI3K signaling and with facultative glucose transporters whose trafficking is PI3K dependent and whose abundance marks cells destined for differentiation. Perturbation of class I PI3K activity disrupts asymmetry of upstream antigen receptors and downstream glucose transporter traffic. The roles of PI3K signaling in nutrient utilization, proliferation, and gene expression may have converged with the conserved role of PI3K signaling in cellular symmetry breaking to form a logic for regenerative lymphocyte divisions.

Metabolic control of cell fate bifurcations in a hematopoietic progenitor population

“…Whether and how sibling progenitor cells might undergo unequal information transfer, such as asymmetric PI3K signaling, will require further investigation. The cell biological mechanism may relate to asymmetric clustering of Flt3 receptor‐associated signaling events or another cell polarity mechanism . Nonetheless, the association between metabolism and hematopoietic cell fate bistability could open new avenues for therapeutic intervention.…”

“…The cell biological mechanism may relate to asymmetric clustering of Flt3 receptor-associated signaling events or another cell polarity mechanism. 10,19 Nonetheless, the association between metabolism and hematopoietic cell fate bistability could open new avenues for therapeutic intervention.…”

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

“…265 long-lived Tm. [272][273][274][275][276][277] Furthermore, inhibition of mTOR by rapamycin supports the formation of CTL memory and other mTOR inhibitors drive the development of high quality and quantity of Tm. [278][279][280][281][282] Some of these findings were surprising as rapamycin was originally considered an immunosuppressive agent.…”

The metabolic spectrum of memory T cells

“…Metabolic parameters are also implicated in the outcomes of asymmetric cell division, which can occur following the activation of T cells by antigen‐presenting cells. Asymmetric cell division is initiated before the T cell begins to divide and results in the daughter cell distal to the antigen‐presenting cells having an increased propensity to develop a memory cell phenotype, whereas the daughter cell proximal to the antigen‐presenting cell is more likely to develop into a short‐lived effector cell During this process, asymmetry in mTORC1 and phosphinositide‐3 kinase activity, expression of cMYC and the amino acid transporter CD98 occurs . Furthermore, in human T cells, asymmetry in the daughter cells can be enhanced through transient inhibition of mTOR signaling .…”

“…Asymmetric cell division is initiated before the T cell begins to divide and results in the daughter cell distal to the antigen-presenting cells having an increased propensity to develop a memory cell phenotype, whereas the daughter cell proximal to the antigen-presenting cell is more likely to develop into a short-lived effector cell 35 During this process, asymmetry in mTORC1 and phosphinositide-3 kinase activity, expression of cMYC and the amino acid transporter CD98 occurs. [36][37][38] Furthermore, in human T cells, asymmetry in the daughter cells can be enhanced through transient inhibition of mTOR signaling. 39 Collectively, these factors implicate metabolic reprogramming in addition to transcriptional programs and epigenetic regulation in determining the fate of activated T cells.…”