IKKbeta is essential for protecting T cells from TNFalpha-induced apoptosis

Immunity. 2001 Mar;14(3):217-30. doi: 10.1016/s1074-7613(01)00104-2.

Abstract

Transcription factor NF-kappaB, whose activation depends on the IKKbeta catalytic subunit of the IkappaB kinase, was assigned with both anti- and proapoptotic functions in T lymphocytes. To critically evaluate these functions, we transferred Ikkbeta-/- or wild-type (wt) fetal liver (FL) stem cells into lethally irradiated mice. Ikkbeta-/- radiation chimeras show thymic rudiments, aberrant lymphoid organs, and absence of T cells. T lymphopoiesis is rescued when Ikkbeta-/- stem cells are cotransferred with wt bone marrow, suggesting that IKKbeta may mediate its lymphopoietic function via extrinsic factors. However, almost normal development of Ikkbeta-/- T cells is observed upon removal of type 1 TNFalpha receptor, indicating that TNFalpha signaling accounts for the absence of Ikkbeta-/- T cells. Indeed, Ikkbeta-/- radiation chimeras exibit elevated circulating TNFalpha, and Ikkbeta-/- thymocytes display increased TNFalpha sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Apoptosis / drug effects*
  • Bone Marrow Transplantation
  • Cell Division / drug effects
  • Flow Cytometry
  • Gene Deletion
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / immunology
  • Hematopoietic Stem Cells / metabolism
  • Hepatocytes / metabolism
  • Hepatocytes / transplantation
  • I-kappa B Kinase
  • Liver / cytology
  • Liver / embryology
  • Lymph Nodes / cytology
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology
  • Mice
  • Myeloid Progenitor Cells / cytology
  • Myeloid Progenitor Cells / metabolism
  • NF-kappa B / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Radiation Chimera / genetics
  • Radiation Chimera / immunology
  • Radiation Chimera / metabolism
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction / drug effects
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / immunology
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / drug effects
  • Thymus Gland / immunology
  • Thymus Gland / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • NF-kappa B
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse