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Histone Deacetylase 7 Licenses Innate Effector Development in iNKT Cells

  • Author(s): Lee, Intelly Shang-Zhi
  • Advisor(s): Verdin, Eric
  • et al.
Abstract

Innate effector lymphocytes, including invariant natural killer T-cells (iNKT), are conserved and integral components of the vertebrate immune system that orchestrate the early host response to infection, yet the mechanisms by which developing thymocytes acquire either a naïve or innate effector identity remain unclear. Here we report that histone deacetylase 7 (HDAC7), a highly conserved signal-dependent transcriptional corepressor abundantly expressed in thymocytes, is a crucial regulatory factor that licenses innate effector development in iNKT cells. In a gain-of-function setting where HDAC7 is constitutively nuclear localized, innate effector development is blocked and iNKT cells become diverted to extremely rare, naïve-like T-cells with limited cytokine production and propensity to recirculate. Conversely, in a loss-of-function setting where HDAC7 is removed via conditional genetic deletion, naïve T-cell development is impeded and more thymocytes acquire an innate effector identity, particularly in an Eomesodermin-expressing CD8 peripheral subset that resembles so-called “innate memory” T-cells. Regulation of this fate decision hinges on the ability of HDAC7 to antagonize the transcriptional activity of Promyelocytic Leukemia Zinc Finger (PLZF), a signature innate effector transcription factor of innate effector development, which we demonstrate occurs in part through upstream transcriptional repression and direct physical binding. Finally, we find that in mice with a gain-of-function HDAC7 transgene which spontaneously develop tissue-specific autoimmunity directed mainly against the hepatobiliary tissues and gastrointestinal mucosa, restoring iNKT cells in vivo can mitigate tissue destruction and reduce mortality rate. These studies identify HDAC7 as an important epigenetic licensing factor that controls naïve versus innate effector development in thymocytes and implicates a heretofore underappreciated role for innate effectors in protecting against autoimmune disease.

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