A central problem faced by multi-cellular organisms is the need for rare progenitor cells to continually produce terminally differentiated cells while also preserving a self-renewing lineage. What mechanisms allow a progenitor cell to give rise to two daughter cells that adopt such different fates? One potential solution is an evolutionarily conserved mechanism called asymmetric cell division, during which a dividing cell imparts unequal inheritance of its components to its two daughter cells, making them different from inception.
From the August 3rd, 2007 issue of Science: Challenges in Immunology
In the mammalian immune system, T lymphocytes face a similar need for simultaneous differentiation and regeneration. While our circulating lymphocytes are collectively capable of recognizing virtually any microbial invader, the price paid for this breadth of recognition is an extremely limited number of lymphocytes specific for any given microbe. During a microbial infection, a naïve lymphocyte, so called because it has never encountered its foreign antigen, must give rise to two distinct classes of cellular progeny:terminally differentiated effector cells that provide acute protection and self-renewing memory cells that provide long-lived immunity. Our lab seeks to understand the mechanisms underlying specification of these disparate fates. We have found that T lymphocytes exploit an evolutionarily conserved process—asymmetric cell division—during the course of an immune response in order to generate the diverse cell fates required for robust immunity (Science 2007). In addition, asymmetric inheritance of a fate-determining transcription factor, T-bet, during mitosis enables nascent daughter cells to adopt distinct fates from inception (Immunity 2011, JCI 2017). Importantly, the mechanism underlying T-bet asymmetry appears to involve asymmetric segregation of the cellular degradation machinery, the proteasome.
We have applied single-cell gene expression measurements from CD8+ T lymphocytes sequentially after microbial infection in vivo to identify transcriptional signatures that control the eventual fates of these cells (Nature Immunology 2014; Nature Immunology 2017; Science Immunology 2020). We have also utilized single-cell approaches aimed at improving the molecular understanding of the inflammatory bowel diseases and identifying new diagnostic and therapeutic targets for these diseases (Science Immunology 2020; NEJM 2020). We anticipate our research will contribute to our understanding of a multitude of processes, including stem cell and tissue regeneration, immunity, autoimmunity, and cancer.