2018 Theses Doctoral
Asymmetric Cell Division in the Generation of Immunity and Tolerance
The immune system relies on the collaboration of heterogeneous cell types to respond to infection, develop immunological memory, and to maintain immunological tolerance. In response to infection, naïve lymphocytes must divide and give rise to differentiated effector cells while also regenerating a population of memory cells that may respond more efficiently to future infection. It has been demonstrated in B cells and T cells that the generation of these cell types may be accomplished simultaneously through asymmetric cell division. The second chapter of this thesis focuses on what factors may drive the divergence of cell fates in asymmetric cell division of CD8+ T cells. We demonstrate unequal expression of transcription factor TCF1 between cytokinetic sibling cells, which may be driven by unequal transduction of nutrient-sensitive PI3K/AKT/mTOR signaling. In chapter three, we extend our interrogation of asymmetric cell division in lymphocytes to the development of regulatory T cells, which are important for the maintenance of immunological self-tolerance. It has been shown that there is some overlap in the T cell receptor repertoires of Tregs and conventional CD4+ T cells. We propose that this overlap may be a result of an asymmetric cell division, giving rise to one Treg and one conventional CD4+ T cell. We demonstrate asymmetric Foxp3 expression between cytokinetic sibling cells found in the thymus as well as from an in vitro Treg induction model. We also show that in vitro upregulation of Foxp3, the major Treg-associated transcription factor, is inhibited by cell cycle inhibitors, further linking the act of cell fate divergence to a divisional event.
- Yen_columbia_0054D_14417.pdf application/pdf 12.8 MB Download File
More About This Work
- Academic Units
- Cellular, Molecular and Biomedical Studies
- Thesis Advisors
- Reiner, Steven L.
- Ph.D., Columbia University
- Published Here
- January 26, 2018