INTERLEUKIN-6 INFLUENCES GERMINAL CENTER DEVELOPMENT AND ANTIBODY-PRODUCTION VIA A CONTRIBUTION OF C3 COMPLEMENT COMPONENT

Mice rendered deficient for interleukin (IL) 6 by gene targeting were evaluated for their response to T cell-dependent antigens. Antigen-spe cific immunoglobulin (Ig)M levels were unaffected whereas all IgG isot ypes showed varying degrees of alteration. Germinal center reactions o ccurred but remained physically smaller in comparison to those in the wild-type mice. This concurred with the observations that molecules in volved in initial signaling events leading to germinal center formatio n 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 ce ll (Th) 1 versus Th2 cytokines observed. However, B7.1 molecules, abse nt from wild-type counterparts, were detected on germinal center B cel ls isolated from the deficient mice suggesting a modification of costi mulatory signaling. A second alteration involved impaired de novo synt hesis of C3 both in serum and germinal center cells from IL-6-deficien t mice. Indeed, C3 provided an essential stimulatory signal for wild-t ype germinal center cells as both monoclonal antibodies that interrupt ed C3-CD21 interactions and sheep anti-mouse C3 antibodies caused a si gnificant decrease in antigen-specific antibody production. In additio n, germinal center cells isolated from C3-deficient mice produced a si milar defect in isotype production. Low density cells with dendritic m orphology were the local source IL-6 and not the germinal center lymph ocytes. Adding IL-6 in vitro to IL-6-deficient germinal center cells s timulated cell cycle progression and increased levels of antibody prod uction. These findings reveal that the germinal center produces and us es molecules of the innate immune system, evolutionarily pirating them in order to optimally generate high affinity antibody responses.