A lymphotoxin-IFN-β axis essential for lymphocyte survival revealed during cytomegalovirus infection

Theresa A. Banks, Sandra Rickert, Chris A. Benedict, Lisa Ma, Mira Ko, Joshua Meier, Won Ha, Kirsten Schneider, Steven W. Granger, Olga Turovskaya, Dirk Elewaut, Dennis Otero, Anthony R. French, Stanley C. Henry, John D. Hamilton, Stefanie Scheu, Klaus Pfeffer, Carl F. Ware

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

The importance of lymphotoxin (LT) βR (LTβR) 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 LTβR 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 LTα expression by hemopoietic cells, independent of developmental defects in lymphoid tissue, whereas LTβR expression by both stromal and hemopoietic cells was needed to prevent apoptosis. The induction of IFN-β was also severely impaired in MCMV-infected LTα-/- mice, but immunotherapy with an agonist LTβR Ab restored IFN-β levels, prevented lymphocyte death, and enhanced the survival of these mice. IFN- αβR-/- 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 LTαβ-dependent pathway important for MCMV host defense.

Original languageEnglish
Pages (from-to)7217-7225
Number of pages9
JournalJournal of Immunology
Volume174
Issue number11
DOIs
StatePublished - Jun 1 2005

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