T lymphocytes, a group of white blood cells, continually scan our tissues for evidence of infection. They can recognize cells that have been infected and initiate powerful immune responses against these cells as well as against the pathogen responsible for infection. Immature T lymphocytes (also known as thymocytes) have to be "trained" to distinguish uninfected from infected cells. This research team has developed an elaborate system to select young T lymphocytes that have potential to make this distinction from among the millions that are generated daily. This selection process occurs in a specialized organ called the thymus and is a critical step in keeping us safe from autoimmune reactions.
In order to mature successfully, thymocytes must interact extensively with specialized cells known as thymic epithelial cells. These interactions determine which immature T cells can safely enter circulation. This project examines the interesting possibility that mature T lymphocytes, themselves, play a role in shaping these all-important interactions. Using genetically modified mouse strains and a set of imaging tools that can be used to identify and trace cells in the thymus, these investigators will test an original hypothesis that a special group of fully mature T lymphocytes stay in the thymus and enhance the ability of epithelial cells to select the most useful and least dangerous immature T lymphocytes for further maturation. By improving our understanding of the molecular and cellular participants in T cell selection, these studies will shed light on what can go awry and contribute to autoimmune disease.
This investigation will also contribute directly and significantly to the training of young scientists. The studies described will be performed exclusively by undergraduates, who were also the inspiration for the project. The investigator has a very strong track record of educating young scientists: 95% of the seventy-five senior undergraduates mentored in her lab over the last sixteen years have pursued post-graduate studies in medicine, research, education, and public health.
We are very grateful NSF for funding our studies on blood cell development - studies that were performed entirely with very talented undergraduate students, the majority of whom are now pursuing careers in medicine and research. These students co-authored a paper that is in press in Stem Cells that sheds light on the signals that help blood stem cells make decisions. Most of our blood cells are short lived and have to made continually through life. However, they all originate from a special group of stem cells, hematopoietic stem cells, that are very long lived and, in fact, last as long as we live. These stem cells are typically very quiet and last long by "laying low". However, they also have the ability to give rise to two kinds of "daughter cells" - those that are just like them and become long-lived stem cells and those that go on to divide and give rise to all blood cell types - red and white. Red blood cells carry oxygen to our tissues and white blood cells protect us from infection. White blood cells are very diverse and include the myeloid group, which attack pathogens very quickly and with little discrimination, and the lymphoid group which takes longer to be armed, but are exquisitely specific and can remember the invader so that it doesn't make us sick the next time it infects. We were interested in understanding what how a blood stem cell decides to replenish itself or chooses to mature into a myeloid or lymphoid cell. Our previous work, funded by NSF over the last fifteen years, suggested that the protein Nur77, was centrally involved in helping young mouse blood cells make fateful decisions. This turned out to be the case not only for young lymphoid cells, but also for even younger blood stem cells. Ruben Land, the lead author of the study (at the computer in the photo), started this work as an undergraduate at Haverford College and continued it when we shifted our laboratory to Columbia University in New York. He helped our lab initiate a collaboration with Dr. Peter Klein's laboratory at the University of Pennsylvania - and tirelessly traveled between three cities to complete the study with the help of recent Haverford graduates Anna Rayne (standing in the photo) and Ashley Vanderbeck. Briefly, our work shows that the most immature blood cells express this interesting protein Nur77. Those that express the most tend to be the 'quietest', a characteristic of long lasting stem cells. When we grafted Nur77 expressing immature blood cells into another mouse, they gave rise to all blood cells and replenished themselves - showing that there were, in fact, long-lived stem cells. Many of us in this field assume that long-lived stem cells give rise to both lymphoid and myeloid white blood cell types without discrimination - and we were pleased to discover another "marker" for such long-lived cells. Surprisingly, however, when we looked closely, the long-lived Nur77+ cells gave rise predominantly to one type of white blood cell - the myeloid and not lymphoid cell type. Our results lend support to claims by other labs that at least some of our stem cells can be biased. Some of our long-lived stem cells are multi-potent, but our and other work show that some prefer to give rise to myeloid cells (they are "myeloid-biased"), some to lymphoid cells (they are "lymphoid biased"). The students' work identified a novel marker for myeloid-biased stem cells. We also showed that this marker is responding to specific signals in the tissue where stem cells reside - the bone marrow. These signals tend to be "stressors" coming from very specific parts of the bone marrow and may be priming these cells for a quick attack. This work should allow us to pinpoint where such myeloid-biased cells exist and understand how what is responsible for their bias. Ultimately, this work will contribute to larger efforts aimed at customizing our immune response to infection and the regulation of blood cancers. We are very pleased that the funded work resulted in such an exciting publication, but even more pleased that it allowed our undergraduates to be full participants rather than 'visitors' to the research process: making observations in our genetically modified mouse model, raising questions, advancing hypotheses and ideas for experiments, running the experiments, troubleshooting results, repeating and running the experiments again. They traveled to present their work at national conferences (including the Keystone Symposium on Hematopoiesis in early 2013), wrote the first drafts of the manuscript, fielded reviews,resubmitted revisions, and were thrilled to receive the wonderful news of its acceptance in Stem Cells. They are skilled and inspiring 'products' of the very valuable support that the NSF-RUI and taxpayers provide for STEM education in the United States. Thank you.
