2017 Theses Doctoral

Asymmetric metabolism by sibling lymphocytes coupling differentiation and self-renewal

Chen, Yen-Hua

After naïve lymphocytes are activated by foreign antigens, they yield cellular progeny with diverse functions, including memory cells, effector cells, and precursors of germinal center B cells. However, it remains unclear whether a naïve lymphocyte is capable of generating daughter cells with multiple fates or multiple naive cells are activated and each give rise to daughter cells with different cell fates. This dissertation analyzes the role of asymmetric cell division in the generation of effector lymphocytes and maintenance of progenitor cells. Our data provide evidence that daughter cells exhibit differential mitochondrial stasis and inherit different amounts of glucose transporters, which is coupled to distinct metabolic and transcriptional program in the sibling cells.
To uncover the links between mitochondrial stasis, transcription network reprogramming and cell fate, we perturbed mitochondrial clearance with pharmacological and genetic approaches. I found that the treatments, which impaired mitochondrial function, increased the differentiation of B cells and T cells into effector subsets. Thus, we hypothesize that mitochondrial stasis could be a trigger for effector cell differentiation. To further explore the mechanism for aged mitochondria-induced shifts in transcriptional and metabolic programs, we used reactive oxygen species (ROS) scavengers and glycolysis inhibitors to demonstrate that mitochondria function and the expressions of lineage-specific transcription factors crosstalk through ROS-mediated signaling and activating AMPK. ROS scavenger treatments helped to maintain the progenitor population and suppressed the differentiation of effector subsets, whereas effector cell differentiation was boosted in the AMPK-α1 knockout. These results suggest mitochondrial stress-induced ROS is required for repressing Pax5 and increasing IRF4.
In addition to showing mitochondrial stasis’ connection to cell fate, this dissertation also demonstrates the linkage between phosphatidylinositol-3-kinases and glucose transporter 1 (Glut1) in establishing polarity in dividing cells and in transcriptional reprogramming.
In sum, this dissertation suggests that asymmetric mitochondrial stasis and nutrient up-take could be part of the driving force of cell fate owing to self-reinforcement and reciprocal inhibition between anabolism and catabolism. These results shed light on the deterministic mechanism of effector cell differentiation and provide clues to the basis of maintenance of self-renewal by activated lymphocytes. These findings could be beneficial for producing memory cells and preventing effector cell exhaustion phenotype in a chronic infection or in cancer microenvironment.