The goal of this proposal is to understand the molecular mechanisms that control ?? T cell commitment and the link between commitment and effector fate specification. There is growing evidence suggesting that ?? T cell commitment is influenced by differences in T cell receptor (TCR) signal strength. These differences in TCR signal strength instruct fate through induction of Id3, an inhibitor of E protein DNA binding. Whil E proteins have a clear role in regulating lineage fate decisions, the downstream target genes that these E proteins control, as well as the transcriptional regulators that cooperate to mediate this process, remain unknown. These fate decisions are too complex to focus on a single gene or pathway and require a comprehensive, network-based approach. ?? T cell effector fate is also specified in the thymus and is influenced by TCR signaling; however, the relationship between commitment to the ?? T cell lineage and acquisition of effector fate has not been formally tested. Efforts to gain insight into the molecular mechanisms that govern ?? T cell commitment, as well as the link between commitment and effector fate specification, have been confounded by the lack of a molecular indicator that identifies ?? T cell progenitors that have irreversibly committed to ?? T cell lineage. CD73 has recently been identified as a marker of committed ?? T cell progenitors and will be utilized to address these questions.
In Aim 1, uncommitted and committed ??TCR+ progenitors will be isolated based on CD73 expression to construct a comprehensive, genome-wide network of E protein targets and cooperating transcription factors associated with ?? T cell commitment that will then be tested for their rols in orchestrating ?? lineage commitment.
In Aim 2, TCR signaling will be altered concurrent with and following commitment to the ?? T cell lineage to determine if commitment and effector fate are assigned simultaneously or sequentially. Collectively, these efforts will provide critical insiht into how development of ?? T cells is controlled.
?? T cells play crucial roles in controlling inflammation, maintaining epithelial barriers, and eradicating cutaneous malignancies that are unique and non-overlapping with ?? T cells. Understanding the mechanisms that control ?? T cell commitment and effector fate specification may allow for the manipulation of ?? T cell activity fr therapeutic benefit.
| Fahl, Shawn P; Coffey, Francis; Kain, Lisa et al. (2018) Role of a selecting ligand in shaping the murine ??-TCR repertoire. Proc Natl Acad Sci U S A 115:1889-1894 |
