Id3 Restricts {gamma}{delta} NKT Cell Expansion by Controlling Egr2 and c-Myc Activity [IMMUNE SYSTEM DEVELOPMENT]

NKT cells are neonatal-derived T lymphocytes that are grouped together with invariant NKT cells based on their shared innate-like developmental program characterized by the transcription factor PLZF (promyelocytic leukemia zinc finger). Previous studies have demonstrated that the population size of NKT cells is tightly controlled by Id3-mediated inhibition of E-protein activity in mice. However, how E proteins promote NKT cell development and expansion remains to be determined. In this study, we report that the transcription factor Egr2, which also activates PLZF expression in invariant NKT cells, is essential for regulating NKT cell expansion. We observed a higher expression of Egr family genes in NKT cells compared with the conventional T cell population. Loss of function of Id3 caused an expansion of NKT cells, which is accompanied by further upregulation of Egr family genes as well as PLZF. Deletion of Egr2 in Id3-deficient NKT cells prevented cell expansion and blocked PLZF upregulation. We further show that this Egr2-mediated NKT cell expansion is dependent on c-Myc. c-Myc knockdown attenuated the proliferation of Id3-deficient NKT cells, whereas c-Myc overexpression enhanced the proliferation of Id3/Egr2–double-deficient NKT cells. Therefore, our data reveal a regulatory circuit involving Egr2–Id3–E2A, which normally restricts the population size of NKT cells by adjusting Egr2 dosage and c-Myc expression.

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