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Journal of Virology, March 2002, p. 2375-2383, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2375-2383.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Role of an Intact Splenic Microarchitecture in Early Lymphocytic Choriomeningitis Virus Production

*** Stefan Müller,1 Lukas Hunziker,2 Susanne Enzler,1 Myriam Bühler-Jungo,1 James P. Di Santo,3 Rolf M. Zinkernagel,2 and C. Mueller1*

Department of Pathology, University of Bern, CH-3010 Bern,1 Institute for Experimental Immunology, University of Zurich, CH-8091 Zurich, Switzerland,2 Institut Pasteur, F-75724 Paris, France3

Received 6 September 2001/ Accepted 27 November 2001

An acute infection with lymphocytic choriomeningitis virus (LCMV) is efficiently controlled by the cytotoxic-T-cell (CTL) response of the host, and LCMV titers in the spleen and peripheral solid organs usually fall sharply after day 4 to 6 postinfection. Surprisingly, infection of immunodeficient recombination-activating gene 2-deficient (RAG2-/-) mice with 5 x 102 PFU of LCMV-WE causes about 80-fold-lower LCMV titers in the spleen on day 4 postinfection compared with C57BL/6 control mice. This could not be attributed to NK cell activity, since common gamma-chain-deficient RAG2-/- mice lacking NK cells show low LCMV titers comparable to those for RAG2-/- mice. Furthermore, the reduced early LCMV production in spleens could not be explained by an enhanced gamma interferon production in RAG2-/- mice. Analysis of mutant mice exhibiting various defects in the splenic microarchitecture, including (i) tumor necrosis factor alpha-negative (TNF-{alpha}-/-), lymphotoxin alpha-negative (LT{alpha}-/-), B-cell-deficient µMT mice, (ii) immunoglobulin M-negative mice, and (iii) RAG-/- mice reconstituted with wild-type versus TNF-{alpha}-/- LT{alpha}-/- B cells, revealed a clear correlation between an intact splenic marginal zone, rapid early replication of LCMV in the spleen, and efficient CTL induction. These results suggest that by the preferential infection of the highly organized splenic microarchitecture, LCMV seems to successfully exploit one of the key elements in the chain of the adaptive immune system. Not only does the early tropism of LCMV for the splenic marginal zone trigger a potent immune response, but at the same time the marginal zone may also become a target of early CTL-mediated immunopathology that impairs immune responsiveness.

* Corresponding author. Mailing address: Institute of Pathology, Division of Immunopathology, University of Bern, Murtenstrasse 31, CH-3010 Bern, Switzerland. Phone: 41-31-632 89 04. Fax: 41-31-381 87 64. E-mail: christoph.mueller{at}pathology.unibe.ch.

Journal of Virology, March 2002, p. 2375-2383, Vol. 76, No. 5
0022-538X/02/$04.00+0     DOI: 10.1128/jvi.76.5.2375-2383.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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