Extraordinary advances are being made in our understanding of the immune system, with discovery of functionally specialized cell types. However, new data are beginning to reveal that the process by which hematopoietic stem cells (HSC) develop is more complex and less rigidly controlled than generally believed. Textbooks have long depicted simple relationships between HSC and B lymphocytes, but it now appears that there is not just one branch point where progenitors lose the option of becoming B cells and are directed to other fates. Rather, dedication and firm commitment to the B lineage is a gradual process and can be dramatically altered in response to environmental cues. There is still much to learn about endogenous cues such as those provided by cytokines, hormones and cell adhesion molecules. In addition, we have new observations suggesting that retinoids can accelerate the process of lymphocyte formation and their effects on the bone marrow merit further study. For example, these widely prescribed drugs hold promise as agents for boosting recovery of the immune system. We are combining special knock-in mice with cell sorting, cell culture and transplantation techniques to systematically investigate these and other questions. Our lab discovered that Toll-like receptors (TLR) are expressed on hematopoietic cells, allowing these cells to recognize bacterial/viral products and several important outcomes of this interaction have already been identified. For example, TLR ligands stimulate stem cells to enter cycle and begin differentiating, while myeloid restricted cells complete their maturation. The ligands arrest B cell production and cause lymphocyte progenitors to generate several types of dendritic cells. While these new mechanisms may have survival value, we believe there are also circumstances where stem and progenitor cells need to be protected from such substances. Our lab is using defined culture conditions to study mechanisms associated with an apparent re-programming of lymphoid progenitors. In addition, we are tracking the same phenomena in HSV infected mice. Project Narrative: Our bone marrow must constantly make new blood cells, including cells responsible for antibody formation and defense against infections. Patients are vulnerable to infections following chemotherapy or transplantation, but our data suggest that it may be possible to accelerate recovery of the immune system. Basic understanding of early stages of immune system development may point the way to improved healing of damaged tissues as well as better treatments for cancer and autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020069-28
Application #
8011449
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Nasseri, M Faraz
Project Start
1982-09-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
28
Fiscal Year
2011
Total Cost
$399,391
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Iida, Ryuji; Welner, Robert S; Zhao, Wanke et al. (2014) Stem and progenitor cell subsets are affected by JAK2 signaling and can be monitored by flow cytometry. PLoS One 9:e93643
Welner, Robert S; Kincade, Paul W (2014) 9-1-1: HSCs respond to emergency calls. Cell Stem Cell 14:415-6
Zhang, Qingzhao; Esplin, Brandt L; Iida, Ryuji et al. (2013) RAG-1 and Ly6D independently reflect progression in the B lymphoid lineage. PLoS One 8:e72397
Satoh, Yusuke; Yokota, Takafumi; Sudo, Takao et al. (2013) The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages. Immunity 38:1105-15
Zhang, Qingzhao; Iida, Ryuji; Yokota, Takafumi et al. (2013) Early events in lymphopoiesis: an update. Curr Opin Hematol 20:265-72
Ichii, Michiko; Frank, Mark Barton; Iozzo, Renato V et al. (2012) The canonical Wnt pathway shapes niches supportive of hematopoietic stem/progenitor cells. Blood 119:1683-92
Shimazu, Tomoyuki; Iida, Ryuji; Zhang, Qingzhao et al. (2012) CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential. Blood 119:4889-97
Luis, T C; Ichii, M; Brugman, M H et al. (2012) Wnt signaling strength regulates normal hematopoiesis and its deregulation is involved in leukemia development. Leukemia 26:414-21
Zhang, Qingzhao; Iida, Ryuji; Shimazu, Tomoyuki et al. (2012) Replenishing B lymphocytes in health and disease. Curr Opin Immunol 24:196-203
Esplin, Brandt L; Shimazu, Tomoyuki; Welner, Robert S et al. (2011) Chronic exposure to a TLR ligand injures hematopoietic stem cells. J Immunol 186:5367-75

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