Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus

Toll-like receptor (TLR)-dependent pathways control the production of IFNalphabeta, a key cytokine in innate immune control of viruses including mouse cytomegalovirus (MCMV). The lymphotoxin (LT) alphabeta-LTbeta receptor signaling pathway is also critical for defense against MCMV and thought to aid...

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Published in:Cell host & microbe 2008-02, Vol.3 (2), p.67-76
Main Authors: Schneider, Kirsten, Loewendorf, Andrea, De Trez, Carl, Fulton, James, Rhode, Antje, Shumway, Heather, Ha, Sukwon, Patterson, Ginelle, Pfeffer, Klaus, Nedospasov, Sergei A, Ware, Carl F, Benedict, Chris A
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - metabolism
Herpesviridae Infections - immunology
Immunity, Innate
Interferon Type I - metabolism
Lymphotoxin alpha1, beta2 Heterotrimer - deficiency
Lymphotoxin alpha1, beta2 Heterotrimer - genetics
Lymphotoxin alpha1, beta2 Heterotrimer - metabolism
Lymphotoxin beta Receptor - metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Murine cytomegalovirus
Muromegalovirus - immunology
NF-kappaB-Inducing Kinase
Protein Serine-Threonine Kinases - metabolism
Receptor Cross-Talk
Receptors, Tumor Necrosis Factor
Signal Transduction
Spleen - immunology
Stromal Cells - immunology
Stromal Cells - metabolism
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Summary:Toll-like receptor (TLR)-dependent pathways control the production of IFNalphabeta, a key cytokine in innate immune control of viruses including mouse cytomegalovirus (MCMV). The lymphotoxin (LT) alphabeta-LTbeta receptor signaling pathway is also critical for defense against MCMV and thought to aid in the IFNbeta response. We find that upon MCMV infection, mice deficient for lymphotoxin (LT)alphabeta signaling cannot mount the initial part of a biphasic IFNalphabeta response, but show normal levels of IFNalphabeta during the sustained phase of infection. Significantly, the LTalphabeta-dependent, IFNalphabeta response is independent of TLR signaling. B, but not T, cells expressing LTbeta are essential for promoting the initial IFNalphabeta response. LTbetaR expression is required strictly in splenic stromal cells for initial IFNalphabeta production to MCMV and is dependent upon the NF-kappaB-inducing kinase (NIK). These results reveal a TLR-independent innate host defense strategy directed by B cells in communication with stromal cells via the LTalphabeta cytokine system.
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2007.12.008