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

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