TNF activation of NF-κB is essential for development of single-positive thymocytes

J Exp Med. 2016 Jul 25;213(8):1399-407. doi: 10.1084/jem.20151604. Epub 2016 Jul 18.

Abstract

NF-κB activation has been implicated at multiple stages of thymic development of T cells, during which it is thought to mediate developmental signals originating from the T cell receptor (TCR). However, the Card11-Bcl10-Malt1 (CBM) complex that is essential for TCR activation of NF-κB in peripheral T cells is not required for thymocyte development. It has remained unclear whether the TCR activates NF-κB independent of the CBM complex in thymocyte development or whether another NF-κB activating receptor is involved. In the present study, we generated mice in which T cells lacked expression of both catalytic subunits of the inhibitor of κB kinase (IKK) complex, IKK1 and IKK2, to investigate this question. Although early stages of T cell development were unperturbed, maturation of CD4 and CD8 single-positive (SP) thymocytes was blocked in mice lacking IKK1/2 in the T cell lineage. We found that IKK1/2-deficient thymocytes were specifically sensitized to TNF-induced cell death in vitro. Furthermore, the block in thymocyte development in IKK1/2-deficient mice could be rescued by blocking TNF with anti-TNF mAb or by ablation of TNFRI expression. These experiments reveal an essential role for TNF activation of NF-κB to promote the survival and development of single positive T cells in the thymus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / immunology
  • Mice
  • Mice, Transgenic
  • NF-kappa B / genetics
  • NF-kappa B / immunology*
  • Receptors, Antigen / genetics
  • Receptors, Antigen / immunology*
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / immunology
  • Thymocytes / cytology
  • Thymocytes / immunology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology*

Substances

  • NF-kappa B
  • Receptors, Antigen
  • Receptors, Tumor Necrosis Factor, Type I
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse