The Multiple Roles of Id2 and Id3 in Invariant NKT Cell Development and NKT Lymphoma Formation in Mice

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Date

2014

Authors

Li, Jia

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Krangel, Michael S.

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Abstract

Invariant NKT (iNKT) cells represent a unique group of αβ T cells that have been classified based on their exclusive usage of the invariant Vα14Jα 18 TCRα –chain and their innate–like effector function. Thus far, the transcriptional programs that control Vα14Jα18 TCRα rearrangements and the population size of iNKT cells remain incompletely defined.

E protein transcription factors have been shown to play multiple roles in T cell development including lineage commitment, receptor gene recombination, proliferation and lineage choice. Inhibitor of DNA–binding (Id) proteins are the natural inhibitors of E protein transcription factors. The goal of this dissertation is to examine E protein functions in the development of iNKT cells in the mouse after combined deletion of genes encoding E protein inhibitors Id2 and Id3.

We revealed important roles of Id proteins and E proteins in regulating iNKT cell development. Deletion of Id2 and Id3 in T cell progenitors resulted in a partial block at the pre–TCR selection checkpoint and a dramatic increase in numbers of iNKT cells. This increase in iNKT cells is accompanied with a biased rearrangement involving Vα14 to Jα18 recombination at the double–positive stage and enhanced proliferation of iNKT cells. We further demonstrate that a 50 percent reduction of E proteins can cause a dramatic lineage shift from iNKT cells to innate–like gd T cells in Id2 and Id3 double–deficient mice. Collectively, these findings suggest that Id2– and Id3–mediated inhibition of E proteins controls iNKT development by restricting lineage choice and population expansion.

Our study also uncovered a novel role of Id proteins in development of NKT lymphoma. Id deficient NKT cells gradually progresses into NKT lymphoma, a rare form of tumor with no clearly defined etiology. Id and E proteins have been demonstrated to be involved in multiple lymphoma and cancer subtypes, but their role in the development of NKT lymphomas is unexplored. Adoptive transfer experiments confirmed that the malignant cells are able to invade healthy tissues. cDNA Microarray analysis of NKT lymphoma and pre–malignant NKT cells revealed alterations in several cytokine signaling pathways during tumor progression. These findings indicate that regulation of E proteins by Id2 and Id3 may play important roles in the development of NKT lymphoma. To our knowledge, this study represents the first mouse model in which NKT lymphoma develops at such high frequency and fast kinetics. Our double knockout mice provide a unique model to study mechanisms of human NKT lymphoma progression.

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Immunology

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Citation

Li, Jia (2014). The Multiple Roles of Id2 and Id3 in Invariant NKT Cell Development and NKT Lymphoma Formation in Mice. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/8686.

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