Brief homogeneous TCR signals instruct common iNKT progenitors whose effector diversification is characterized by subsequent cytokine signaling

Sabrina Bortoluzzi, Nyambayar Dashtsoodol, Thomas Engleitner, Christoph Drees, Sabine Helmrath, Jonas Mir, Albulena Toska, Michael Flossdorf, Rupert Öllinger, Maria Solovey, Maria Colomé-Tatché, Bahire Kalfaoglu, Masahiro Ono, Thorsten Buch, Tim Ammon, Roland Rad, Marc Schmidt-Supprian

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Innate-like T cell populations expressing conserved TCRs play critical roles in immunity through diverse developmentally acquired effector functions. Focusing on the prototypical lineage of invariant natural killer T (iNKT) cells, we sought to dissect the mechanisms and timing of fate decisions and functional effector differentiation. Utilizing induced expression of the semi-invariant NKT cell TCR on double positive thymocytes, an initially highly synchronous wave of iNKT cell development was triggered by brief homogeneous TCR signaling. After reaching a uniform progenitor state characterized by IL-4 production potential and proliferation, effector subsets emerged simultaneously, but then diverged toward different fates. While NKT17 specification was quickly completed, NKT1 cells slowly differentiated and expanded. NKT2 cells resembled maturing progenitors, which gradually diminished in numbers. Thus, iNKT subset diversification occurs in dividing progenitor cells without acute TCR input but utilizes multiple active cytokine signaling pathways. These data imply a two-step model of iNKT effector differentiation.

Original languageEnglish
Pages (from-to)2497-2513.e9
JournalImmunity
Volume54
Issue number11
DOIs
StatePublished - 9 Nov 2021
Externally publishedYes

Keywords

  • IL-17
  • IL-4
  • PLZF
  • agonist TCR signals
  • cytokine polarization
  • effector differentiation
  • gene expression dynamics
  • iNKT
  • innate T cell development
  • thymus

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