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iNKT subsets differ in their developmental and functional requirements on Foxo1.

Huimin Zhang1, Yuwei Zhang1, Jun Pan1

  • 1Department of Oncology of the First Affiliated Hospital, Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.

Proceedings of the National Academy of Sciences of the United States of America
|November 13, 2021
PubMed
Summary

Forkhead box protein O1 (Foxo1) differentially regulates invariant natural killer T (iNKT) cell subsets. Foxo1 promotes iNKT1 and iNKT2 cell differentiation and function, but not iNKT17 cells, due to distinct IL7R regulation.

Keywords:
Foxo1TSC2developmentfunctioniNKT subsets

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Invariant natural killer T (iNKT) cells are crucial immune regulators.
  • iNKT cells differentiate into iNKT1, iNKT2, and iNKT17 subsets with distinct functions.
  • Mechanisms governing iNKT subset development and function remain incompletely understood.

Purpose of the Study:

  • To investigate the role of forkhead box protein O1 (Foxo1) in the development and function of iNKT cell subsets.
  • To determine if Foxo1 differentially impacts iNKT1, iNKT2, and iNKT17 cell differentiation and effector functions.

Main Methods:

  • Analysis of IL7R expression in iNKT subsets.
  • Investigation of Foxo1's role in IL7R regulation via transcription factors like RORγt.
  • Assessment of Foxo1's impact on mTORC1 activation and metabolic gene expression patterns.
  • Functional assays to evaluate effector functions of iNKT subsets.

Main Results:

  • Foxo1 promotes iNKT1 and iNKT2 cell differentiation by regulating IL7R expression, but not iNKT17 cells.
  • RORγt, not Foxo1, drives IL7R expression in iNKT17 cells.
  • Foxo1 is essential for iNKT1 and iNKT2 effector functions via mTORC1 activation, but dispensable for iNKT17 cells.
  • iNKT17 cells exhibit distinct metabolic profiles compared to iNKT1 and iNKT2 cells, reflecting differential Foxo1 dependency.

Conclusions:

  • iNKT cell subsets exhibit distinct developmental and functional requirements for Foxo1.
  • Foxo1's role in iNKT cell biology is subset-specific, mediated through differential regulation of IL7R and mTORC1.
  • Understanding these subset-specific mechanisms provides insights into iNKT cell-mediated immune responses.