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Although there are
many examples (e.g. immune deviation) where enhanced cellular
responses correspond with lower humoral responses, here we demonstrate
for the first time two models in which cytotoxic T lymphocyte
(CTL) activity is associated with an enhanced antibody response.
First, C57BL/6 mice generate a stronger antibody response to ovalbumin
DNA immunization than congenic bm1 mice. The latter differ from
C57BL/6 mice in that the H-2Kb molecule is mutated so that the
immunodominant CTL epitope of ovalbumin is no longer presented.
Second, pre-existing CTLs (induced by ovalbumin peptide-priming)
increased the antibody response to a second unrelated antigen
(beta-galactosidase) co-immunized with ovalbumin. One possible
mechanism is that CTLs may release antigen from DNA transfected
cells by killing or damaging them, and this freed antigen is then
accessible to dendritic cells and B cells. Our finding of CTL-mediated
antibody enhancement has important implications for tumor and
viral immunobiology and vaccination.
Figure
1: a) OVA peptide (OVAp)-priming increased the antibody response
to beta-galactosidase co-immunized with OVA DNA immunization.
Eight week old male C57BL/6 mice (n=8) were primed with either
OVAp or control insulin peptide (INSp) in complete Freund’s
adjuvant. After two weeks, all mice were immunized by gene gun
with pellets co-coated with plasmids encoding OVA and beta-galactosidase.
Two and four weeks later, IgG antibodies against beta-galactosidase
were higher (p=0.001) in mice primed with OVAp, compared with
those primed with the control INSp. After 12 weeks, beta-galactosidase
antibodies remained significantly higher (p=0.01) in mice primed
with OVAp compared to INSp. b) Twelve days after OVAp-priming,
mice (n=8) were treated with anti-CD8 antibody (0.5mg 53.6.7 and
0.5mg YTS169 i.p.) or not. All mice were co-immunized with OVA
and beta-galactosidase DNA two days later. Three weeks after that,
ELISA titers of anti-beta-galactosidase responses were determined.
c) Pre-existing herpes simplex virus (HSV)-specific CTLs increase
the antibody response to beta-galactosidase when co-expressed
with OVA-hsv (in which the CTL epitope OVAp is replaced with HSVp).
Eight-week-old male C57BL/6 mice were peptide-primed with HSVp.
After three weeks, mice were DNA-immunized with pellets co-coated
with beta-galactosidase plasmid plus either OVA or OVA-hsv. HSVp-primed
mice had higher beta-galactosidase antibodies (p=0.01) after co-immunization
with OVA-hsv compared with OVA.
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