SOX13, A γδ T Cell-Specific Gene, Is a WNT-Signaling Antagonist Regulating T Cell Development: A Dissertation
Authors
Melichar, Heather J.Faculty Advisor
Leslie J. Berg, Ph.D.Academic Program
Immunology and MicrobiologyUMass Chan Affiliations
PathologyDocument Type
Doctoral DissertationPublication Date
2006-05-19Keywords
T-LymphocytesGenes
T-Cell Receptor gamma
Genes
T-Cell Receptor delta
Stem Cells
Cell Differentiation
Autoantigens
High Mobility Group Proteins
Transcription Factors
Amino Acids, Peptides, and Proteins
Cells
Genetic Phenomena
Hemic and Immune Systems
Metadata
Show full item recordAbstract
Mature αβ and γδ T cells arise from a common precursor population in the thymus. Much debate has focused on the mechanism of T cell lineage choice made by these multi-potential precursor cells. It is widely believed that the decision of these precursor cells to commit to the γδ or αβ T cell lineages is regulated primarily by a specific instructive signal relayed through the appropriate T cell receptor. Contrary to this model, we present evidence for a TCR-independent lineage commitment process. Comparison of global gene expression profiles from immature αβ and γδ lineage thymocytes identified Sox13, an HMG-box transcription factor, as a γδ T cell-specific gene. Unlike other HMG-box transcription factors such as TCF1, LEF1 and SOX4, that are critical for proper αβ T cell development, Sox13 expression is restricted to early precursor subsets and γδ lineage cells. Importantly, SOX13 appears to influence the developmental fate of T cell precursors prior to T cell receptor expression on the cell surface. Transgenic over-expression of Sox13 in early T cell precursors strongly inhibits αβ lineage development, in part, by inhibiting precursor cell proliferation and concomitantly, leading to increased cell death among αβ lineage subsets. Steady-state γδ T cell numbers, however, appear unaffected. Strikingly, the DP αβ lineage cells that do develop in Sox13 transgenic mice are imprinted with a γδ- or precursor-like molecular profile, suggesting that SOX13 plays an active role in the lineage fate decision process or maintenance. Sox13-deficient mice, on the other hand, have selectively reduced numbers of γδ thymocytes, indicating that SOX13 is essential for proper development of γδ T cells. We present additional data demonstrating that SOX13 is a canonical WNT signaling antagonist modulating TCF1 activity, raising a strong possibility that WNT signals, and their modulators, are at the nexus of γδ versus αβ T cell lineage commitment.DOI
10.13028/69tk-7d12Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31560Notes
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Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/69tk-7d12