TWEAK attenuates the transition from innate to adaptive immunity

Heather Maecker; Eugene Varfolomeev; Frank Kischkel; David Lawrence; Heidi LeBlanc; Wyne Lee; Stephen Hurst; Dimitry Danilenko; Jun Li; Ellen Filvaroff; Becky Yang; Dylan Daniel; Avi Ashkenazi

doi:10.1016/j.cell.2005.09.022

TWEAK attenuates the transition from innate to adaptive immunity

Cell. 2005 Dec 2;123(5):931-44. doi: 10.1016/j.cell.2005.09.022.

Authors

Heather Maecker¹, Eugene Varfolomeev, Frank Kischkel, David Lawrence, Heidi LeBlanc, Wyne Lee, Stephen Hurst, Dimitry Danilenko, Jun Li, Ellen Filvaroff, Becky Yang, Dylan Daniel, Avi Ashkenazi

Affiliation

¹ Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

PMID: 16325585
DOI: 10.1016/j.cell.2005.09.022

Abstract

Innate immunity is the first line of defense against infection, protecting the host during the development of adaptive immunity and critically affecting the nature of the adaptive response. We show that, in contrast to tumor necrosis factor alpha (TNF-alpha), the related protein TWEAK attenuates the transition from innate to adaptive mechanisms. TWEAK-/- mice had overabundant natural killer (NK) cells and displayed hypersensitivity to bacterial endotoxin, with their innate immune cells producing excess interferon (IFN)-gamma and interleukin (IL)-12. TWEAK inhibited stimulation of the transcriptional activator STAT-1 and induced p65 nuclear factor (NF)-kappaB association with histone deacetylase 1, repressing cytokine production. TWEAK-/- mice developed oversized spleens with expanded memory and T helper 1 (TH1) subtype cells upon aging and mounted stronger innate and adaptive TH1-based responses against tumor challenge. Thus, TWEAK suppresses production of IFN-gamma and IL-12, curtailing the innate response and its transition to adaptive TH1 immunity.

MeSH terms

Animals
Cells, Cultured
Cytokine TWEAK
Endotoxins / immunology
Histone Deacetylase 1
Histone Deacetylases / metabolism
Humans
Hypersensitivity / immunology
Immunity, Cellular / physiology*
Immunity, Innate / physiology*
Interferon-gamma / immunology
Interleukin-12 / immunology
Killer Cells, Natural / immunology
Leukocytes, Mononuclear / cytology
Leukocytes, Mononuclear / immunology
Mice
Mice, Knockout
Receptors, Tumor Necrosis Factor / genetics
Receptors, Tumor Necrosis Factor / metabolism
STAT1 Transcription Factor / metabolism
Spleen / anatomy & histology
Spleen / immunology
T-Lymphocyte Subsets / immunology
TWEAK Receptor
Transcription Factor RelA / metabolism
Tumor Necrosis Factor-alpha / immunology*
Tumor Necrosis Factors / genetics
Tumor Necrosis Factors / immunology*

Substances

Cytokine TWEAK
Endotoxins
Receptors, Tumor Necrosis Factor
STAT1 Transcription Factor
Stat1 protein, mouse
TWEAK Receptor
Tnfsf12 protein, mouse
Transcription Factor RelA
Tumor Necrosis Factor-alpha
Tumor Necrosis Factors
Interleukin-12
Interferon-gamma
Hdac1 protein, mouse
Histone Deacetylase 1
Histone Deacetylases