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Purification and Expansion of Mouse Invariant Natural Killer T Cells for in vitro and in vivo Studies
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Purification and Expansion of Mouse Invariant Natural Killer T Cells for in vitro and in vivo Studies

Published on: February 15, 2021

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TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells

Ageliki Tsagaratou1, Edahí González-Avalos1, Sini Rautio2

  • 1Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.

Nature Immunology
|November 22, 2016
PubMed

Insights

Deleting Tet2 and Tet3 in mouse T cells disrupts invariant natural killer T cell (iNKT) development. These Tet2-Tet3 double-knockout iNKT cells expand uncontrollably, indicating TET proteins are crucial for iNKT cell maturation and proliferation control.

Area of Science:

  • Immunology
  • Epigenetics
  • Cell Biology

Background:

  • TET proteins are key epigenetic regulators, catalyzing the oxidation of 5-methylcytosine (5mC) in DNA.
  • Invariant natural killer T cells (iNKT cells) are crucial immune cells involved in immune regulation and surveillance.

Purpose of the Study:

  • To investigate the role of TET proteins, specifically Tet2 and Tet3, in the development and function of iNKT cells.
  • To elucidate the impact of TET protein deficiency on iNKT cell lineage specification and proliferation.

Main Methods:

  • Utilized a mouse model with simultaneous deletion of Tet2 and Tet3 in CD4+CD8+ thymocytes.
  • Analyzed iNKT cell development, proliferation, DNA methylation, and gene expression.
  • Performed adoptive transfer of knockout iNKT cells into recipient mice to assess their in vivo behavior.

Main Results:

  • Simultaneous deletion of Tet2 and Tet3 led to dysregulated iNKT cell development and proliferation.
  • Tet2-Tet3 double-knockout (DKO) iNKT cells showed skewing toward the NKT17 lineage, increased DNA methylation, and impaired T-bet and ThPOK expression.
  • Transferred DKO iNKT cells exhibited uncontrolled expansion dependent on CD1d, suggesting TCR-mediated aberrant proliferation.

Conclusions:

  • TET proteins are essential regulators of iNKT cell fate, ensuring proper development and maturation.
  • TET proteins suppress aberrant iNKT cell proliferation, likely through modulation of TCR signaling pathways.
  • Deficiency in TET proteins leads to dysregulated iNKT cell expansion, highlighting their critical role in maintaining immune homeostasis.

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