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Axis Essential for Lymphocyte Survival Revealed during Cytomegalovirus Infection1
Divisions of*
Molecular Immunology and
Developmental Immunology, La Jolla Institute for Allergy and Immunology, and
Allimmune, San Diego, CA 92121;
Division of Biology and University of California San Diego Cancer Center, University of California at San Diego, La Jolla, CA 92093;¶
Division of Pediatric Rheumatology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110;||
Department of Veterans Affairs, Medical Research Service and Research Center on AIDS and HIV Infection, Durham, NC 27705; and#
Institute of Medical Microbiology, University of Düsseldorf, Düsseldorf, Germany
The importance of lymphotoxin (LT) 
R (LTR) 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 LTR 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
expression by hemopoietic cells, independent of developmental defects in lymphoid tissue, whereas LTR expression by both stromal and hemopoietic cells was needed to prevent apoptosis. The induction of IFN- was also severely impaired in MCMV-infected LT–/– mice, but immunotherapy with an agonist LTR Ab restored IFN- levels, prevented lymphocyte death, and enhanced the survival of these mice. IFN-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-dependent pathway important for MCMV host defense.
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