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 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.
Schneider
Kirsten
K
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology 9420 Athena Circle, La Jolla, CA 92037, USA.
Loewendorf
Andrea
A
De Trez
Carl
C
Fulton
James
J
Rhode
Antje
A
Shumway
Heather
H
Ha
Sukwon
S
Patterson
Ginelle
G
Pfeffer
Klaus
K
Nedospasov
Sergei A
SA
Ware
Carl F
CF
Benedict
Chris A
CA
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D006566:Herpesviridae Infections / Q000276:immunology*; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism*; D053361:Lymphotoxin alpha1, beta2 Heterotrimer / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020239:Receptor Cross-Talk; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology* / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D007370:Interferon Type I; D053361:Lymphotoxin alpha1, beta2 Heterotrimer; D053259:Lymphotoxin beta Receptor; D017346:Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor; D000097782:NF-kappaB-Inducing Kinase