A lymphotoxin-IFN-beta axis essential for lymphocyte survival revealed during cytomegalovirus infection.
The importance of lymphotoxin (LT) betaR (LTbetaR) as a regulator of lymphoid organogenesis is well established, but its role in host defense has yet to be fully defined. In this study, we report that mice deficient in LTbetaR signaling were highly susceptible to infection with murine CMV (MCMV) and early during infection exhibited a catastrophic loss of T and B lymphocytes, although the majority of lymphocytes were themselves not directly infected. Moreover, bone marrow chimeras revealed that lymphocyte survival required LTalpha expression by hemopoietic cells, independent of developmental defects in lymphoid tissue, whereas LTbetaR expression by both stromal and hemopoietic cells was needed to prevent apoptosis. The induction of IFN-beta was also severely impaired in MCMV-infected LTalpha(-/-) mice, but immunotherapy with an agonist LTbetaR Ab restored IFN-beta levels, prevented lymphocyte death, and enhanced the survival of these mice. IFN-alphabetaR(-/-) mice were also found to exhibit profound lymphocyte death during MCMV infection, thus providing a potential mechanistic link between type 1 IFN induction and lymphocyte survival through a LTalphabeta-dependent pathway important for MCMV host defense.
Banks
Theresa A
TA
Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Rickert
Sandra
S
Benedict
Chris A
CA
Ma
Lisa
L
Ko
Mira
M
Meier
Joshua
J
Ha
Won
W
Schneider
Kirsten
K
Granger
Steven W
SW
Turovskaya
Olga
O
Elewaut
Dirk
D
Otero
Dennis
D
French
Anthony R
AR
Henry
Stanley C
SC
Hamilton
John D
JD
Scheu
Stefanie
S
Pfeffer
Klaus
K
Ware
Carl F
CF
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000276:immunology*; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology
C505886:LTB protein, human; C505697:LTBR protein, human; C505887:Ltb protein, mouse; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D017471:Receptors, Interferon; D018124:Receptors, Tumor Necrosis Factor; C505914:TNFSF14 protein, human; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta