Regulation of T cell development by RasGRPs 1 and 3

• Author / Creator

  Golec, Dominic P

• 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.

• Subjects / Keywords

  • Thymus
  • Immunology
  • T cell development

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3M32NQ4F

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. 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.