title: TNF activation of NF-κB is essential for development of single-positive thymocytes.
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.
authors.affiliation: Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, England, UK.
authors.forename: Louise V
authors.identifier: 0000-0001-6806-5589
authors.initials: LV
authors.lastname: Webb
authors.affiliation: Francis Crick Institute, Mill Hill Laboratories, London NW7 1AA, England, UK.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ley
authors.affiliation: 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.
authors.forename: Benedict
authors.identifier: 0000-0003-4352-3373
authors.initials: B
authors.lastname: Seddon
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
chemical_list: D016328:NF-kappa B; D011946:Receptors, Antigen; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse