During an immune response against a microbial pathogen, nave T lymphocytes that recognize the microbe must give rise to two distinct types of progeny. Effector cells serve to provide acute host defense, whereas memory cells provide the ability to mount rapid recall responses should the host re-encounter the pathogen. Prior studies have demonstrated that a single nave CD8+ T lymphocyte is capable of generating all of the diverse cellular fates necessary for an immune response. The process by which a single activated T lymphocyte yields effector- and memory-fated progeny, and the timing at which these differentiation pathways begin to diverge, however, remains unanswered. We have recently shown that a T lymphocyte can undergo asymmetric division to give rise to two daughter cells that are differentially fated toward the effector and memory lineages. The overall goals of the active parent R01 grant are to investigate the functional consequences of asymmetric CD8+ T cell division and to elucidate the mechanisms by which asymmetric division leads to specification of the effector and memory T cell fates. In this revision application, we propose to develop novel single cell approaches to define the transcriptomic and epigenetic roadmap of an individual CD8+ T lymphocyte as it differentiates in vivo in response to a microbial pathogen. Accomplishment of the aims proposed herein is likely to yield important insights into the fundamental mechanisms by which asymmetric division influences cell fate specification and function, and may help to provide a framework for the rational development of vaccines.
Effector and memory T lymphocytes are cells of the immune system that provide protection against microbes. Our goal is to understand how these cells are generated and how they function. We propose to use cutting-edge technologies that enable us to derive an enormous amount of genomic information from individual cells. These studies may help our efforts to improve vaccines.
|Kakaradov, Boyko; Arsenio, Janilyn; Widjaja, Christella E et al. (2017) Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing. Nat Immunol 18:422-432|
|Song, Yan; Botvinnik, Olga B; Lovci, Michael T et al. (2017) Single-Cell Alternative Splicing Analysis with Expedition Reveals Splicing Dynamics during Neuron Differentiation. Mol Cell 67:148-161.e5|
|Widjaja, Christella E; Olvera, Jocelyn G; Metz, Patrick J et al. (2017) Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification. J Clin Invest 127:3609-3623|
|Bertin, Samuel; Aoki-Nonaka, Yukari; Lee, Jihyung et al. (2017) The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1. Gut 66:1584-1596|
|Klann, Jane E; Remedios, Kelly A; Kim, Stephanie H et al. (2017) Talin Plays a Critical Role in the Maintenance of the Regulatory T Cell Pool. J Immunol 198:4639-4651|
|Schobel, Seth A; Stucker, Karla M; Moore, Martin L et al. (2016) Respiratory Syncytial Virus whole-genome sequencing identifies convergent evolution of sequence duplication in the C-terminus of the G gene. Sci Rep 6:26311|
|Metz, Patrick J; Lopez, Justine; Kim, Stephanie H et al. (2016) Regulation of Asymmetric Division by Atypical Protein Kinase C Influences Early Specification of CD8(+) T Lymphocyte Fates. Sci Rep 6:19182|
|Shilts, Meghan H; Rosas-Salazar, Christian; Tovchigrechko, Andrey et al. (2016) Minimally Invasive Sampling Method Identifies Differences in Taxonomic Richness of Nasal Microbiomes in Young Infants Associated with Mode of Delivery. Microb Ecol 71:233-42|
|Banno, Asoka; Garcia, Daniel A; van Baarsel, Eric D et al. (2016) Downregulation of 26S proteasome catalytic activity promotes epithelial-mesenchymal transition. Oncotarget 7:21527-41|
|Ngoi, Soo M; Lopez, Justine M; Chang, John T (2016) The Microtubule-Associated Protein Lis1 Regulates T Lymphocyte Homeostasis and Differentiation. J Immunol 196:4237-45|
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