The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/6/2157/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 12, June 16, 1997 2157-2170

Articles

On the Key Role of Secondary Lymphoid Organs in Antiviral Immune Responses Studied in Alymphoplastic (aly/aly) and Spleenless (Hox11–/–) Mutant Mice

Urs Karrer*, Alana Althage*, Bernhard Odermatt{ddagger}, Charles W.M. Roberts§, Stanley J. Korsmeyer§, Shigeki Miyawaki||, Hans Hengartner*, and Rolf M. Zinkernagel*

From the * Institute of Experimental Immunology, Department of Pathology, University Hospital of Zürich, 8091 Zürich, Switzerland; {ddagger} Laboratory for Special Techniques, Department of Pathology, University of Zürich, 8091 Zürich, Switzerland; § Howard Hughes Medical Institute and Departments of Medicine and Pathology, Washington University School of Medicine, St. Louis, Missouri 63110; and || Molecular Biology Department, Research Laboratories, Nippon Shinyaku Co., Ltd., Nishioji-Hachijo, Minami-ku, Kyoto 601, Japan

The role of the spleen and of other organized secondary lymphoid organs for the induction of protective antiviral immune responses was evaluated in orphan homeobox gene 11 knockout mice (Hox11–/–) lacking the spleen, and in homozygous alymphoplastic mutant mice (aly/aly) possessing a structurally altered spleen but lacking lymph nodes and Peyer's patches. Absence of the spleen had no major effects on the immune response, other than delaying the antibody response by 1–2 d. In aly/aly mice, the thymus-independent IgM response against vesicular stomatitis virus (VSV) was delayed and reduced, whereas the T-dependent switch to the protective IgG was absent. Therefore, aly/aly mice were highly susceptible to VSV infection. Since aly/aly spleen cells yielded neutralizing IgM and IgG after adoptive transfer into recipients with normally structured secondary lymphoid organs, these data suggest that the structural defect was mainly responsible for inefficient T–B cooperation. Although aly/aly mice generated detectable, but reduced, CTL responses after infection with vaccinia virus (VV) and lymphocytic choriomeningitis virus (LCMV), the elimination of these viruses was either delayed (VV) or virtually impossible (LCMV); irrespective of the dose or the route of infection, aly/aly mice developed life-long LCMV persistence. These results document the critical role of organized secondary lymphoid organs in the induction of naive T and B cells. These structures also provide the basis for cooperative interactions between antigen-presenting cells, T cells, and B cells, which are a prerequisite for recovery from primary virus infections via skin or via blood.

Address correspondence to Urs Karrer, Institute of Experimental Immunology, Department of Pathology, University of Zürich, Schmelzbergstr. 12, 8091 Zürich, Switzerland.

1Abbreviations used in this paper: aly/aly, homozygous alymphoplastic mutant mice; aly/+, heterozygous normal littermates; B6, C57BL/6 mice; DC, dendritic cells; FDC, follicular DC; GC, germinal centers; Hox11–/–, orphan homeobox gene 11 knockout mice; IDC, interdigitating DC; IND, serotype Indiana; IND-G, glycoprotein of VSV IND; LCMV, lymphocytic choriomeningitis virus; MAdCAM-1, mucosal addressin cell adhesion molecule 1; MM, marginal metallophils; MOI, multiplicity of infection; MZ, marginal zone; MZM, MZ macrophages; PP, Peyer's patches; RPM, red pulp macrophages; TI, thymus independent; VaccINDG, VV recombinant for IND-G; VSV, vesicular stomatitis virus; VV, vaccinia virus.


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