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Zhang B , Jiao A , Dai M , Wiest DL , Zhuang Y
Id3 Restricts gammadelta NKT Cell Expansion by Controlling Egr2 and c-Myc Activity
J Immunol. 2018 Sep 1;201(5) :1452-1459
PMID: 30012846    PMCID: PMC6103809    URL: https://www.ncbi.nlm.nih.gov/pubmed/30012846
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gammadelta NKT cells are neonatal-derived gammadelta 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 gammadelta NKT cells is tightly controlled by Id3-mediated inhibition of E-protein activity in mice. However, how E proteins promote gammadelta 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 gammadelta NKT cell expansion. We observed a higher expression of Egr family genes in gammadelta NKT cells compared with the conventional gammadelta T cell population. Loss of function of Id3 caused an expansion of gammadelta NKT cells, which is accompanied by further upregulation of Egr family genes as well as PLZF. Deletion of Egr2 in Id3-deficient gammadelta NKT cells prevented cell expansion and blocked PLZF upregulation. We further show that this Egr2-mediated gammadelta NKT cell expansion is dependent on c-Myc. c-Myc knockdown attenuated the proliferation of Id3-deficient gammadelta NKT cells, whereas c-Myc overexpression enhanced the proliferation of Id3/Egr2-double-deficient gammadelta NKT cells. Therefore, our data reveal a regulatory circuit involving Egr2-Id3-E2A, which normally restricts the population size of gammadelta NKT cells by adjusting Egr2 dosage and c-Myc expression.
1550-6606 Zhang, Baojun ORCID: http://orcid.org/0000-0002-7786-4304 Jiao, Anjun ORCID: http://orcid.org/0000-0002-5688-818X Dai, Meifang Wiest, David L ORCID: http://orcid.org/0000-0002-0792-3188 Zhuang, Yuan ORCID: http://orcid.org/0000-0002-2964-3654 R01 GM059638/GM/NIGMS NIH HHS/United States R21 AG034457/AG/NIA NIH HHS/United States Journal Article United States J Immunol. 2018 Jul 16. pii: jimmunol.1800106. doi: 10.4049/jimmunol.1800106.