Lymphocyte Fate and Metabolism: A Clonal Balancing Act

Abstract

Activated lymphocytes perform a clonal balancing act, yielding a daughter cell that differentiates owing to intense PI3K signaling, alongside a self-renewing sibling cell with blunted anabolic signaling. Divergent cellular anabolism versus catabolism is emerging as a feature of several developmental and regenerative paradigms. Metabolism can dictate cell fate, in part, because lineage-specific regulators are embedded in the circuitry of conserved metabolic switches. Unequal transmission of PI3K signaling during regenerative divisions is reminiscent of compartmentalized PI3K activity during directed motility or polarized information flow in non-dividing cells. The diverse roles of PI3K pathways in membrane traffic, cell polarity, metabolism, and gene expression may have converged to instruct sibling cell feast and famine, thereby enabling clonal differentiation alongside self-renewal.

Keywords: PI3K; anabolism; asymmetric; catabolism; mTOR; self-renewal.

Figure 1. Metabolism is a bistable process that is suited to binary or branching cellular decisions

In single-celled beings, nutrients are utilized when available for proliferative metabolism and when nutrients are limiting cells undertake a fundamentally different, starvation metabolism. In animals, some cells are in an anabolic and proliferative state because of strong growth factor signaling and licensure to take up excess nutrients, while some cells are in a catabolic and quiescent state owing to survival signaling with limiting nutrient uptake. Each state has feed-forward and feedback self-reinforcement and inhibits the processes of the other side. Consequently, perturbation of a subcomponent of one state topples that state and results in a switch to the other sate. Therefore, cells tend to be in equilibrium in one or the other state. For a non-dividing cell such a macrophage, phenotypic switching into inflammatory and non-inflammatory behavior is driven by anabolic versus catabolic signaling, respectively. For regenerative paradigms such as lymphocytes or epithelial replacement, anabolism and catabolism drive differentiation and self-renewal, respectively. The metabolic states appear deterministic of the cell fates because of interdependency in their signaling pathways. For example, lymphocyte self-renewal is wired into the PI3K pathway because FoxO1 maintains expression of key cell identity genes. Conversely, IRF4 drives lymphocyte differentiation because it plays an obligatory role in aerobic glycolysis and the anabolic switch required for proliferation and differentiation. Blue hexagons represent nutrients and blue transmembrane brackets represent nutrient transporters.

Figure 2. Hypothetical model for diversifying activation state and cell fate through asymmetric cell division

(a) The two wells represent two states of metabolic equilibrium: the red cell is catabolic, quiescent, and undifferentiated; the blue cells are anabolic, proliferative and irreversibly differentiated. Purple cell at summit represents an unstable intermediate state that is more anabolic than the red cell but not irreversibly differentiated, thus capable of rolling backward or forward. (b, c) Upon activation, the red cell begins to roll uphill and divide. Asymmetric signaling during division produces a red daughter cell with weaker activation, which rolls back downhill, and purple daughter cell with stronger anabolic activation, which continues upward to summit. (d) The mitotic, anabolic, purple cell has also become asymmetric. After division, the purple cell, with lesser activation, balances at the summit and the more activated blue cell, which has crossed the threshold into irreversible differentiation, rolls forward downhill. The red cell might be considered a quiescent stem cell that does not directly produce a fully differentiated cell. The purple cell might be considered an active progenitor --- more proliferative and anabolic than the red cell, but not yet irreversibly differentiated. The blue cell cannot roll backwards under physiological conditions because it has undergone irreversible differentiation, although the blue cells will eventually become post-mitotic.

Figure 3. Asymmetric PI3K signaling is an evolutionarily conserved regulator of cell polarity

Spatially restricted domains of PI3K activity (blue lines) are characteristic of numerous forms of symmetry-breaking. Usually in response to an extrinsic cue, a self-reinforcing signaling domain is nucleated by the concerted actions of PI3K and regulated actin remodeling. A common feature of these systems is having diametrically opposite localization of negatively-acting domains (red lines) that dampen PI3K activity or stabilize actin. Centrosome and microtubule organizing centers (black) are often polarized and act as hubs or counterbalances to the polarized PI3K activity and actin dynamics. Processes as diverse as directed cell migration, neuronal polarity, apico-basal polarity, asymmetric division, and lymphocyte activation, function, and regeneration are controlled in this manner. It is speculated that activating recycling endosomes (blue ovals) maintain an asymmetric position at one end of the spindle pole, leading to asymmetric inheritance of signaling endosomes during mitosis.

Figure 4. Key Figure. Diverse roles of PI3K signaling may converge to shape the logic of cell fate branches

The ability of PI3K-mediated membrane trafficking and polarity to function in in concert with other PI3K activities, such as cell growth, proliferation, metabolism and gene regulation, may underlie the ability of progenitor cells to differentiate and self-renew (or create two different types of differentiated daughter cells). Asymmetric cell divisions are an integral process in metazoan growth and repair. Seemingly, not all instances of asymmetric division are dependent on the PAR polarity network. It is speculated that a metabolic asymmetry network may represent a complementary or cooperative system to ensure unequal outcomes from a cell division.