Modulation of Id3 induces a fetal-specific HEB-dependent gamma delta T cell developmental pathway in the adult mouse thymus

• Published in: The Journal of immunology (1950) Vol. 202; no. 1_Supplement; pp. 53 - 53.14
• Main Authors: Selvaratnam, Johanna Samantha, Anderson, Michele K
• Format: Journal Article
• Language: English
• Published: 01.05.2019
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.202.Supp.53.14

Abstract Gamma delta T cells (γδ T cells) are key players in tissue barrier homeostasis and immunity. Understanding the molecular mechanisms by which γδ T cells are programmed to develop into the γδT17 lineage is essential to develop strategies for controlling IL-17 activity during pathogenic conditions. Previously we showed that the E protein transcription factor HEB is an essential regulator of the γδT17 lineage, and that the generation of fetal γδT17 cells occurs through a HEB-dependent fetal-restricted pathway that does not involve upregulation of CD73 (Pathway 2). Id3, an antagonist of E proteins, inhibits key regulators of γδT17 development. Therefore, we hypothesized that the loss of Id3 would enhance γδT17 development. We characterized adult Id3-RFP knock-in mice, and found that the Id3−/− recapitulated the previously established expansion of Vγ1+ γδ T cells. However, the adult Id3+/− thymus showed a re-emergence of Pathway 2, suggesting that reduced Id3 levels promotes the fetal HEB-dependent γδT17 program. Moreover, there was an increase in Vγ1-Vγ4- γδ T cells, which suggests the appearance of Vγ6+ cells that are normally restricted to the fetal thymus. Interestingly, Vγ4+ cells and Vγ1-Vγ4-cells in Id3+/− mice displayed Pathway 2 profiles, while Vγ1+ cells exhibited the normal adult thymic developmental profile leading to mature CD73+ γδ T cells in both Id3+/− and Id3−/− mice. Future studies will examine whether reduced HEB in the Id3+/− mice inhibits Pathway 2 in the adult thymus, and obtain more definitive evidence as to whether the Id3+/− γδ T cells in the adult thymus develop toward the IL-17 fate. In conclusion, our studies indicate that the balance between E proteins and Id3 regulates the developmental programming pathway of γδ T cells.