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.
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). Importantly, the mechanism underlying T-bet asymmetry appears to involve asymmetric segregation of the cellular degradation machinery, the proteasome. In collaboration with Gene Yeo’s lab at UCSD, we have recently applied single-cell gene expression measurements from CD8+ T lymphocytes early after microbial infection in vivo to identify transcriptional signatures predictive of the eventual fates of these cells (Nature Immunology 2014). We have also recently demonstrated a functional role for asymmetric division, mediated by the polarity protein atypical PKC, in specification of memory lymphocyte fates (Journal of Immunology 2015). We anticipate our research will contribute to our understanding of a multitude of processes, including embryonic patterning, organ formation and function, stem cell and tissue regeneration, immunity, and cancer.