Specification of CD8+ T lymphocyte fates during adaptive immunity revealed by single cell gene expression analyses (P1448)

Abstract

Abstract Although it is well established that heterogeneity of lymphocyte fate is an essential feature of adaptive immune responses, how and when these divergent cellular fates are specified remains unknown. It has been previously shown that a T lymphocyte responding to a microbial infection can undergo asymmetric division to yield two daughter cells that are differentially fated from inception. Such a model suggests that the progeny arising from each of the two differentially fated daughter cells might exhibit distinct patterns of gene expression. Because strategies analyzing bulk cell populations cannot distinguish differences among individual cells, we applied high-throughput single cell gene expression profiling to interrogate single CD8+ T lymphocytes throughout the course of an immune response to a bacterial infection. We demonstrate that terminally differentiated effector cells and self-renewing memory cells exhibit unique gene expression profiles. Moreover, we are able to identify cells early during the immune response, beginning with the first cell division, that exhibit distinct gene expression patterns characteristic of effector or memory cells. Finally, we derive a network model that allows us to predict the sequential activation of genes that orchestrate each cellular fate, providing a comprehensive view of CD8+ T lymphocyte differentiation. Together, these results provide novel insights into the specification of lymphocyte fates during an immune response.