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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
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.
Key Words: germinal center • interleukin 6 • complement • antibody • follicular dendritic cells
Address all correspondence to M.H. Kosco-Vilbois at her present address: Serono Pharmaceutical Research Institute, 14, chemin des Aulx, CH-1228 Geneva, Switzerland. Phone: 41-22-706-9708. Fax: 41-22-794-6965. E-mail: marie.kosco-vilbois{at}serono.com
S. Herren's present address is Serono Pharmaceutical Research Institute, CH-1228 Geneva, Switzerland.
Abbreviations used: BCR, B cell antigen receptor; FDC, follicular dendritic cell; HA, hemagglutinin; HPRT, hypoxanthine phosphoribosyltransferase; PNA, peanut agglutinin; RT, reverse transcription.
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