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J. Exp. Med.,
Volume 188, Number 10, November 16, 1998 1895-1906
By
From the * Basel Institute for Immunology, CH-4005 Basel, Switzerland; Mice rendered deficient for interleukin (IL) 6 by gene targeting were evaluated for their response to T cell-dependent antigens. Antigen-specific immunoglobulin (Ig)M levels were unaffected whereas all IgG isotypes showed varying degrees of alteration. Germinal center reactions occurred but remained physically smaller in comparison to those in the wild-type mice.
This concurred with the observations that molecules involved in initial signaling events leading
to germinal center formation were not altered (e.g., B7.2, CD40 and tumor necrosis factor
R1). T cell priming was not impaired nor was a gross imbalance of T helper cell (Th) 1 versus
Th2 cytokines observed. However, B7.1 molecules, absent from wild-type counterparts, were
detected on germinal center B cells isolated from the deficient mice suggesting a modification
of costimulatory signaling. A second alteration involved impaired de novo synthesis of C3 both
in serum and germinal center cells from IL-6-deficient mice. Indeed, C3 provided an essential
stimulatory signal for wild-type germinal center cells as both monoclonal antibodies that interrupted C3-CD21 interactions and sheep anti-mouse C3 antibodies caused a significant decrease in antigen-specific antibody production. In addition, germinal center cells isolated from
C3-deficient mice produced a similar defect in isotype production. Low density cells with dendritic morphology were the local source of IL-6 and not the germinal center lymphocytes.
Adding IL-6 in vitro to IL-6-deficient germinal center cells stimulated cell cycle progression
and increased levels of antibody production. These findings reveal that the germinal center
produces and uses molecules of the innate immune system, evolutionarily pirating them in order to optimally generate high affinity antibody responses.
Geneva Biomedical
Research Institute, Glaxo Wellcome Research and Development, CH-1228 Geneva, Switzerland; § Max-Planck Institute for Molecular Genetics, Berlin, D-14195 Germany; and Immunological
Medicine Unit, Hammersmith Hospital, London W12 0NN, United Kingdom
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