E proteins control the development of NKγδT cells through their invariant T cell receptor

Ariana Mihai, Sang Yun Lee, Susan Shinton, Mitchell I. Parker, Alejandra V. Contreras, Baojun Zhang, Michele Rhodes, Roland L. Dunbrack, Juan Carlos Zúñiga-Pflücker, Maria Ciofani, Yuan Zhuang, David L. Wiest

Research output: Contribution to journalArticlepeer-review


T cell receptor (TCR) signaling regulates important developmental transitions, partly through induction of the E protein antagonist, Id3. Although normal γδ T cell development depends on Id3, Id3 deficiency produces different phenotypes in distinct γδ T cell subsets. Here, we show that Id3 deficiency impairs development of the Vγ3+ subset, while markedly enhancing development of NKγδT cells expressing the invariant Vγ1Vδ6.3 TCR. These effects result from Id3 regulating both the generation of the Vγ1Vδ6.3 TCR and its capacity to support development. Indeed, the Trav15 segment, which encodes the Vδ6.3 TCR subunit, is directly bound by E proteins that control its expression. Once expressed, the Vγ1Vδ6.3 TCR specifies the innate-like NKγδT cell fate, even in progenitors beyond the normally permissive perinatal window, and this is enhanced by Id3-deficiency. These data indicate that the paradoxical behavior of NKγδT cells in Id3-deficient mice is determined by its stereotypic Vγ1Vδ6.3 TCR complex.

Original languageEnglish
Article number5078
Pages (from-to)5078
JournalNature Communications
Issue number1
StatePublished - Dec 2024


  • Animals
  • T-Lymphocyte Subsets/immunology
  • Signal Transduction
  • Mice, Inbred C57BL
  • Inhibitor of Differentiation Proteins/metabolism
  • Mice
  • Cell Differentiation
  • Receptors, Antigen, T-Cell, gamma-delta/metabolism
  • Mice, Knockout


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