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Regulation of T cell development by RasGRPs 1 and 3 Open Access


Other title
T cell development
Type of item
Degree grantor
University of Alberta
Author or creator
Golec, Dominic P
Supervisor and department
Dr. Troy Baldwin
Examining committee member and department
Foley, Edan (Medical Microbiology and Immunology)
Anderson, Michele (Immunology)
Baker, Kristi (Oncology)
Ostergaard, Hanne (Medical Microbiology and Immunology)
Department of Medical Microbiology and Immunology
Date accepted
Graduation date
2017-11:Fall 2017
Doctor of Philosophy
Degree level
T cell development is a highly dynamic process driven by interactions between developing hematopoietic progenitor cells and numerous cell types that nurture their development. Ultimately, signals detected by developing progenitors lead to the activation of cellular signaling pathways that instruct the development of these cells into mature T cells. One signaling pathway that has proven to be an important regulator of T cell development is the highly conserved Ras pathway. Signals transduced through the Ras pathway regulate numerous cellular processes such as differentiation, proliferation, migration and survival, all of which are important during T cell development. The activation of Ras in T cells has been shown to regulated by members of the Ras guanine nucleotide releasing protein (RasGRP) family, which includes RasGRPs 1, 2, 3 and 4. RasGRP1 has proven to be the most potent regulator of T cell development, however the roles of the remaining family members remain unclear. Another RasGRP family member, RasGRP3, closely resembles RasGRP1 but has not been examined during T cell development. Furthermore, the contribution of RasGRP1 to many of the hallmark events of T cell development has not been examined in detail. Therefore, we sought to explore the roles of RasGRP1 and RasGRP3 throughout T cell development. To determine the contributions of these molecules during T cell development we examined gene knock-out mice deficient in RasGRP1, RasGRP3 and RasGRPs 1 and 3. Global analysis of T cell development was performed, uncovering numerous novel roles of RasGRPs 1 and 3 during T cell development. Immature T cell progenitors originate in the bone marrow (BM) and populate the thymus following migration out of the BM via circulation. Early thymic progenitors (ETPs) are the most immature progenitors found within the thymus and are derived from incoming BM progenitors. Mice deficient in RasGRPs 1 and 3 showed impaired development of ETPs, suggesting that RasGRPs 1 and 3 regulate the earliest stages of T cell development. Downstream of ETPs, early development of CD4-CD8- ‘double negative’ (DN) thymocytes culminates with development through the β-selection checkpoint. We determined that RasGRP1, but not RasGRP3, was critical for efficient passage through thymocyte β-selection. The product of β-selection is the development of the CD4+CD8+ ‘double positive’ (DP) thymocyte population. DP thymocytes expressing a mature αβ T cell receptor (TCR) experience a number of different fates depending on the affinity with which their clonal TCRs bind self-peptides presented on major histocompatibility complex (MHC) molecules. Generally, cells weakly recognizing self-peptide undergo positive selection and develop into mature T cells, while cells strongly recognizing self-peptides undergo negative selection and are eliminated from the T cell repertoire to prevent autoimmunity. However, some cells strongly recognizing self-peptides undergo an alternative positive selection process termed agonist selection. Numerous lineages of cells are derived from agonist selection, including a unique subset of intestinal T cells known as TCRαβ+CD8αα intraepithelial lymphocytes (IELs). Our data indicate that RasGRP1 is critical for the development of TCRαβ+CD8αα IELs through controlling thymocyte agonist selection. Collectively, the examination of RasGRP1 and RasGRP3 activity during T cell development has shed light onto the varied roles of these molecules throughout this complex developmental program.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Golec, D.P., Dower, N.A., Stone, J.C. and Baldwin, T.A. 2013. RasGRP1, but not RasGRP3, is required for efficient thymic β-selection and ERK activation downstream of CXCR4. PLoS One 8: e53300Golec, D.P., Caviedes, L.M.H., and Baldwin, T.A. 2016. RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors. J Immunol 197, 1743-1753Golec, D.P., Hoeppli, R.E., Caviedes, L.M.H., McCann, J., Levings, M.K. and Baldwin, T.A. 2017. Thymic progenitors of TCRαβ+ CD8αα intestinal intraepithelial lymphocytes require RasGRP1 for development. J Exp Med. 214, 2421-2435

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