SOX13, A γδ T Cell-Specific Gene, Is a WNT- Signaling Antagonist Regulating T Cell Development: A Dissertation

Mature af3and yb 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 yb or af3 T cell lineages is regulated primarily by a specific instrctive 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 af3 and yb lineage thymocytes identified Sox13 an HMG-box transcription factor, as a yb T cell-specific gene. Unlike other HMG-box transcription factors such as TCFl , LEFI and SOX4, that are critical for proper af3 T cell development Sox13 expression is restrcted to early precursor subsets and yb 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 inibits af3 lineage development, in part, by inhibiting precursor cell proliferation and concomitantly, leading to increased cell death among af3 lineage subsets. Steady-state yb T cell numbers , however, appear unaffected. Strkingly, the DP af3 lineage cells that do develop in Sox13 transgenic mice are imprinted with a ybor precursor-like molecular profie, 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 yb thymocytes, indicating that SOX13 is essential for proper development of yb T cells. We present additional data demonstrating that SOX13 is a canonical WNT signaling antagonist modulating TCFl activity, raising a strong possibility that WNT signals, and their modulators , are at the nexus of yb versus af3 T cell lineage commtment.