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

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

Author information

1
Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, England, UK.
2
Francis Crick Institute, Mill Hill Laboratories, London NW7 1AA, England, UK.
3
Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, England, UK benedict.seddon@ucl.ac.uk.

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.

PMID:
27432943
PMCID:
PMC4986527
DOI:
10.1084/jem.20151604
[Indexed for MEDLINE]
Free PMC Article

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