Abstract
T cell activation involves the orchestration of several signaling pathways, including that of the 'classical' transcription factor NF-kappaB components NF-kappaB1-RelA. The function of the 'nonclassical' NF-kappaB2-RelB pathway is less clear, although T cells lacking components of this pathway have activation defects. Here we show that mice deficient in NF-kappaB-inducing kinase have a complex phenotype consisting of immunosuppression mediated by CD25(-)Foxp3(-) memory CD4(+) cells and, in the absence of those cells, hyper-responsive naive CD4(+) T cells, which caused autoimmune lesions after adoptive transfer into hosts deficient in recombination-activating genes. Biochemical studies indicated involvement of a cell-intrinsic mechanism in which NF-kappaB2 (p100) limits nuclear translocation of NF-kappaB1-RelA and thereby functions as a regulatory 'brake' for the activation of naive T cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus
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Adoptive Transfer
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Animals
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / transplantation
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Cells, Cultured / cytology
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Cells, Cultured / immunology
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DNA-Binding Proteins / deficiency
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Forkhead Transcription Factors / analysis
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Gene Expression Regulation*
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Hyaluronan Receptors / analysis
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Immunologic Memory / physiology
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Interleukin-2 / physiology
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Lymphocyte Activation
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Mice
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Mice, Inbred Strains
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NF-kappa B p50 Subunit / metabolism
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NF-kappa B p52 Subunit / physiology*
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NF-kappaB-Inducing Kinase
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Protein Serine-Threonine Kinases / deficiency
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Transcription Factor RelA / metabolism
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Transcription Factor RelB / deficiency
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Transcription Factor RelB / metabolism
Substances
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Cd44 protein, mouse
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Hyaluronan Receptors
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Interleukin-2
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NF-kappa B p50 Subunit
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NF-kappa B p52 Subunit
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Rag2 protein, mouse
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Rela protein, mouse
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Relb protein, mouse
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Transcription Factor RelA
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Nfkb1 protein, mouse
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Transcription Factor RelB
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Protein Serine-Threonine Kinases