Regulation and Derailment of an Innate-like T Cell Thymic Developmental Pathway
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2018
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Invariant Natural Killer T (iNKT) and γδNKT cells are well-characterized innate-like counterparts of αβ and γδ T cells respectively that express semi-invariant T cell receptors (TCRs) and are capable of mounting rapid immune responses. Although many key regulatory molecules have been shown to play important roles in the development of these cells, the mechanism of their lineage specification and acquisition of effector functions remain to be fully addressed.
Id proteins, or inhibitor of DNA binding and differentiation, act as antagonists of transcription factors known as E proteins. Id proteins are known promote the differentiation of conventional T cells, and suppress the expansion of innate-like T cells. We have previously found that expansion of iNKT and another subset of innate-like T cells leads to rapid lymphoma development in Id2/Id3-deficient mice. The goal of this dissertation is to elucidate the mechanisms by which Id proteins differentially regulate the lineage choice between the concurrently developing innate and conventional lineages in early stages of T cell development, as well as the mechanisms driving the malignant transformation of these expanding innate-like T cells.
Firstly, I tested the hypothesis whether uninhibited E2A activity in the absence of Id proteins transcriptionally promotes the development of iNKT cells. Indeed, I found E2A-mediated upregulation of critical genes, and biased rearrangement at the DP stage promotes iNKT cell lineage development in Id-deficient mice. The observed expansion of the iNKT cells in these mice is not abrogated by blocking pre-TCR signaling, which is required for conventional αβ T cell development. Finally, E2A is found to be a key transcriptional regulator of both iNKT and γδNKT lineages, which appear to have shared lineage history. Therefore, my study revealed a previously unappreciated role of E2A in the regulation of lineage choice between conventional and innate-like T cell fate as early as the pre-TCR checkpoint.
Second, I explored the origins and pathways that drive innate-like lymphomas in Id2/Id3-deficient mice. I found that CD1dTet- innate-like T cells develop independent of CD1d-mediated selection, and start expansion in neonatal mice. The transcriptional program in expanding neonatal iNKT cells is significantly modified, including upregulation of the cytokine-cytokine receptor interaction pathway which can promote their expansion and migration, ultimately leading to their malignant transformation. I also discovered shared dysregulation of the NF-kB pathway and genes with reported driver mutations between our iNKT-derived lymphomas and human iNKT tumors. My study demonstrates that Id2 plays a tumor suppressive role in collaboration with Id3 in developing T cells in mice. Contrary to the perception of Id proteins as potential therapeutic targets in some cancer models, these results also highlight the possibility of aggravated tumorigenesis upon non-targeted suppression of Id2 and Id3.
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Roy, Sumedha (2018). Regulation and Derailment of an Innate-like T Cell Thymic Developmental Pathway. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/16909.
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