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Dissertation
The functional role of Th-POK in lineage commitment during T-cell development
Doctor of Philosophy (Ph.D.), Drexel University
2010
DOI:
https://doi.org/10.17918/etd-3273
Abstract
T lymphocytes develop in the thymus through multiple stages (DN, DP and SP) during which their survival and lineage are determined. During thymocyte maturation, T-cell Receptor (TCR) signaling induces important downstream mediators of differentiation. ThPOK (T-helper inducing POZ-Kruppel factor) has been identified as a master regulator of lineage commitment at the CD4/CD8 branch point, and is selectively induced in class II-restricted thymocytes, suggesting that it is upregulated by strong TCR signals. In order to identify upstream signaling pathways responsible for ThPOK induction, we mapped key transcriptional control elements at the ThPOK locus. These studies show that a dual silencer/enhancer element is primarily responsible for selective induction of ThPOK. We are currently attempting to identify key factors that bind to and regulate activity of this element during thymocytedevelopment. Given that [gamma][delta] lineage commitment, like CD4 commitment, may be decided by relative TCR signal strength, it is possible that the same downstream effectors may be involved in both processes. However, the potential role of ThPOK in [gamma][delta] commitment has not yet been explored. By carrying out in vitro stimulation of [gamma][delta] thymocytes with anti-TCR antibody and varying ligand affinity for the transgenic KN6 [gamma][delta]TCR in vivo, we have now established that ThPOK induction in [gamma][delta]TCR+ thymocytes is controlled by TCR signaling and specifically requires a strong/ high affinity TCR ligand. Strikingly, ThPOK deficient mice show a severe reduction in mature [gamma][delta] thymocytes as well as altered V region usage in [gamma][delta] thymocytes, showing that ThPOK is important for maturation/selection of [gamma][delta] cells. ThPOK is particularly important for development of a subset of [gamma][delta] thymocytes that express V[gamma]1.1 and the NK1.1 surface marker, which has been previously referred to as NKT[gamma][delta] cells and appears to be enriched for self-reactive specificities. Conversely, in mice that express ThPOK constitutively, the proportion of mature [gamma][delta] thymocytes is greatly increased, as is the proportion of V[gamma]1.1+ thymocytes. These results demonstrate a new role for ThPOK in development of [gamma][delta] thymocytes. Future work will distinguish whether ThPOK is important for differentiation, proliferation and our lineage commitment of the [gamma][delta] subset.
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Details
- Title
- The functional role of Th-POK in lineage commitment during T-cell development
- Creators
- Kyewon Park - DU
- Contributors
- Elisabeth S. Papazoglou (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 3273; 991014632383004721