Asymmetric cell division during T cell development controls downstream fate

Kim Pham, Raz Shimoni, Mirren Charnley, Mandy J. Ludford-Menting, Edwin D. Hawkins, Kelly Ramsbottom, Jane Oliaro, David Izon, Stephen B. Ting, Joseph Reynolds, Grant Lythe, Carmen Molina-Paris, Heather Melichar, Ellen Robey, Patrick O. Humbert, Min Gu, Sarah M. Russell

During mammalian T cell development, the requirement for expansion of many individual T cell clones, rather than merely expansion of the entire T cell population, suggests a possible role for asymmetric cell division (ACD). We show that ACD of developing T cells controls cell fate through differential inheritance of cell fate determinants Numb and α-Adaptin. ACD occurs specifically during the β-selection stage of T cell development, and subsequent divisions are predominantly symmetric. ACD is controlled by interaction with stromal cells and chemokine receptor signaling and uses a conserved network of polarity regulators. The disruption of polarity by deletion of the polarity regulator, Scribble, or the altered inheritance of fate determinants impacts subsequent fate decisions to influence the numbers of DN4 cells arising after the β-selection checkpoint. These findings indicate that ACD enables the thymic microenvironment to orchestrate fate decisions related to differentiation and self-renewal.