Positive and negative selection are the critical forces that shape the T cell repertoire as it is formed in the thymus. This grant addresses the molecular mechanisms of positive selection. It makes use of a model system where defined peptide ligands can be used to preferentially induce one selection outcome or the other. Our previous experiments established that positive selection results from a low affinity TCR interaction with self-peptide ligand; while negative selection results from a high affinity interaction. This application presents and tests the hypothesis that weak interactions generate a sustained biochemical signal compared to strong interactions because they fail to invoke negative feedback mechanisms. In order to study the genetic targets of this weak but sustained signal, we will apply gene array analysis of developmentally distinct populations. Because in our model system, positive selection can be induced with specific peptides, the precise kinetics of gene expression changes can be documented. A final goal of this application relates to how an immature T cell becomes desensitized to those weak interactions that rescued it during development. We will study the role of a specific phosphatase in curtailing the signals generated by low affinity ligands, while leaving those generated by high affinity ligands intact. These results will not only deepen our knowledge of the normal differentiation of T cells, but will aid in establishing the rules whereby immune cells recognize and react to """"""""self"""""""", a topic that has important implication for autoimmune disease.
| Breed, Elise R; Lee, S Thera; Hogquist, Kristin A (2018) Directing T cell fate: How thymic antigen presenting cells coordinate thymocyte selection. Semin Cell Dev Biol 84:2-10 |
| Ruscher, Roland; Hogquist, Kristin A (2018) Intravenous Labeling and Analysis of the Content of Thymic Perivascular Spaces. Bio Protoc 8: |
| Ruscher, Roland; Kummer, Rebecca L; Lee, You Jeong et al. (2017) CD8?? intraepithelial lymphocytes arise from two main thymic precursors. Nat Immunol 18:771-779 |
| Lee, You Jeong; Wang, Haiguang; Starrett, Gabriel J et al. (2015) Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response. Immunity 43:566-78 |
| Jameson, Stephen C; Lee, You Jeong; Hogquist, Kristin A (2015) Innate memory T cells. Adv Immunol 126:173-213 |
| Klein, Ludger; Kyewski, Bruno; Allen, Paul M et al. (2014) Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol 14:377-91 |
| Moran, Amy E; Hogquist, Kristin A (2012) T-cell receptor affinity in thymic development. Immunology 135:261-7 |
| Stritesky, Gretta L; Jameson, Stephen C; Hogquist, Kristin A (2012) Selection of self-reactive T cells in the thymus. Annu Rev Immunol 30:95-114 |
| Moran, Amy E; Holzapfel, Keli L; Xing, Yan et al. (2011) T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J Exp Med 208:1279-89 |
| Weinreich, Michael A; Jameson, Stephen C; Hogquist, Kristin A (2011) Postselection thymocyte maturation and emigration are independent of IL-7 and ERK5. J Immunol 186:1343-7 |
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