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* Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912; and
Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Amsterdam, The Netherlands
The innate immune system uses different mechanisms to respond to infectious pathogens. Experiments evaluating the requirements for a type 1 IFN (IFN-
) response to lymphocytic choriomeningitis virus (LCMV) resulted in the surprising discovery that mice deficient in B and T cell development, i.e., RAG-deficient and SCID, had profoundly reduced levels of IFN- in serum and spleen, despite high viral replication. In addition to lacking an adaptive immune system, these strains exhibit aberrant splenic architecture, and the defect in type 1 IFN production was also observed in mice lacking normal splenic marginal zone (MZ) organization due to genetic deficiencies in B cell development or in cytokine functions required for development of the MZ, i.e., µMT, lymphotoxin-, and TNFR1. Interestingly, the IFN- reduction was not observed after murine CMV infection. Depletion of phagocytic cells from normally developed spleens by treatment with clodronate-containing liposomes demonstrated that these populations were required for the type 1 IFN response to LCMV, but not to murine CMV, and for control of viral replication. Complete repopulation of the MZ was necessary to restore normal IFN- production. In contrast, control of LCMV replication correlated with the return of CD11c+ cells. Taken together, these results demonstrate the complexity and sophistication of the splenic MZ in sensing and responding to particular pathogens and reveal the importance of organ architecture in the production of type 1 IFN.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a National Defense Science and Engineering Graduate Fellowship and National Institutes of Health Grants R01-AI55677 and ROI-CA41268.
2 Address correspondence and reprint requests to Dr. Christine A. Biron, Department of Molecular Microbiology and Immunology, Brown University, Biomed Box G-B6, Providence, RI 02912. E-mail address: Christine_Biron{at}brown.edu
3 Abbreviations used in this paper: DC, dendritic cell; LCMV, lymphocytic choriomeningitis virus; MCMV, murine CMV; MZ, marginal zone; MAdCAM, mucosal addressin cell adhesion molecule; MZM, MZ macrophage; MM, metallophilic macrophage; LT, lymphotoxin; PDC, plasmacytoid DC; SIGN-R, specific intracellular adhesion molecule-grabbing nonintegrin receptor.
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