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. 2000 Jan;74(1):203-8.
doi: 10.1128/jvi.74.1.203-208.2000.

B7 costimulation is critical for antibody class switching and CD8(+) cytotoxic T-lymphocyte generation in the host response to vesicular stomatitis virus

A J McAdam  1 , E A Farkash, B E Gewurz, A H Sharpe
Affiliations

B7 costimulation is critical for antibody class switching and CD8(+) cytotoxic T-lymphocyte generation in the host response to vesicular stomatitis virus

A J McAdam et al. J Virol. 2000 Jan.

Abstract

Antibody and cytotoxic T-lymphocyte (CTL) responses have critical roles in eliminating many viral infections. In addition to stimulation of the T-cell receptor, T cells require costimulatory signals to respond optimally. We evaluated the role of B7 costimulatory molecules (B7-1 and B7-2) in the immune response to viral infection using vesicular stomatitis virus (VSV) and mice lacking either B7-1 or B7-2 or both molecules. Mice lacking both B7-1 and B7-2 had essentially no anti-VSV immunoglobulin G1 (IgG1) response, decreased IgG2a responses, and normal IgM responses, while mice lacking either B7-1 or B7-2 had unaltered anti-VSV antibody responses compared to wild-type mice. Depletion of CD4(+) cells further reduced the IgG2a response in mice lacking both B7 molecules, suggesting that CD4(-) cells may supply help for IgG2a in the absence of B7 costimulation. The absence of both B7 molecules profoundly reduced generation of both primary and secondary VSV-specific class I major histocompatibility complex (MHC)-restricted CTL, whereas VSV-specific CTL responses in mice lacking either B7-1 or B7-2 were similar to those of wild-type animals. Class I MHC-restricted CTL in wild-type mice were not dependent on CD4(+) cells, suggesting that the failure of CTL in the absence of B7s is due to a lack of B7 costimulation directly to the CD8(+) CTL. These data demonstrate that B7-1 and B7-2 have critical, overlapping functions in the antibody and CTL responses to this viral infection.

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Figures

FIG. 1
FIG. 1
The absence of either B7-1 or B7-2 does not significantly alter the antibody response to VSV. Groups of four to seven BALB/c mice were bled for the day 0 assay and then injected with 2 × 106 PFU of VSV i.p. Mice were then bled at the indicated days after VSV infection. Antibody response to VSV was measured by ELISA, and the mouse total Ig or indicated isotype was determined. The mean titers for wild-type, B7-1−/−, and B7-2−/− mice are shown, with the standard deviation of each group indicated. There were no statistically significant differences between any two groups of mice on any day (all P values > 0.05 by two-tailed Student t test). This experiment was performed three times with similar results.
FIG. 2
FIG. 2
The absence of both B7-1 and B7-2 reduces class switching of the antibody response to VSV. Groups of four to seven BALB/c mice were bled and challenged with VSV as described for Fig. 1. The mean titers for wild-type and B7-1/2−/− mice are shown, with the standard deviation of each group indicated. Days at which the responses between wild-type and B7-1/2−/− mice were significantly different are indicated by asterisks (P values < 0.05 by two-tailed Student t test). This experiment was performed four times with similar results.
FIG. 3
FIG. 3
Depletion of CD4+ cells reduces the antibody response to VSV in both wild-type and B7-1/2−/− mice. Groups of three to four BALB/c mice were treated with anti-CD4 or control rat Ig and then injected with 2 × 106 PFU of VSV i.p. Antibody treatment was repeated every 4 to 5 days for 21 days, and then the animals were bled. Antibody response to VSV was measured by ELISA. Panels A and B show antibody responses in four wild-type mice (■, control IgG; □, anti-CD4); and three B7-1/2−/− mice (●, control IgG; ○, anti-CD4), respectively, for the indicated antibody isotypes. This experiment was performed twice with similar results.
FIG. 4
FIG. 4
The absence of both B7-1 and B7-2 reduces primary CTL generation, while the absence of either one of the B7 molecules does not. Groups of three 129S4/SvJae mice were injected with 2 × 106 PFU of VSV i.v. or left untreated as controls (data for a single mouse of each type are shown for clarity; results for all mice within a group were similar). Six days later, the mice were killed and the spleen cells were tested for killing of VSV-infected EL4 targets (top) or uninfected control EL4 targets (bottom) in a 5-h cytotoxicity assay. The VSV-primed mice are indicated by filled symbols, and the uninfected mice are indicated by open symbols. The mice tested were wild type (squares), B7-1−/− (triangles), B7-2−/− (circles), and B7-1/2−/− (diamonds). This experiment was performed three times with similar results.
FIG. 5
FIG. 5
The absence of both B7-1 and B7-2 reduces, but does not abrogate, secondary CTL generation. Wild-type (top) or B7-1/2−/− (bottom) 129S4/SvJae mice (two in each group) were injected with 2 × 106 PFU of VSV i.v. Mice were killed 21 days later, and the pooled spleen cells were stimulated with UV-inactivated VSV-pulsed irradiated splenocytes in the absence or presence of recombinant IL-2 (10 U/ml). Five days later, cultures were tested for killing of VSV-infected targets or uninfected control targets in a 4-h cytotoxicity assay, as indicated on each panel. Symbols: ■, VSV-infected animal with no IL-2 added to culture; ●, VSV-infected animal with IL-2 added to culture; □, uninfected animal with no IL-2 added to culture; ○, uninfected animal with IL-2 added to culture. This experiment was performed three times with similar results.
FIG. 6
FIG. 6
Generation of primary anti-VSV CTL does not depend on CD4+ helper cells. 129S4/SvJae mice (two in each group) were treated with anti-CD4 or control rat Ig and then injected with 2 × 106 PFU of VSV i.v. Antibody treatment was repeated 3 days after infection. Six days after infection, the mice were killed and the pooled spleen cells were tested for killing of VSV-infected targets or uninfected control targets in a 5-h cytotoxicity assay. Symbols: ■, control IgG treated with VSV-pulsed target cells; □, control IgG treated with unpulsed target cells; ●, anti-CD4 treated with VSV-pulsed target cells; ○, anti-CD4 treated with unpulsed target cells. This experiment was performed three times with similar results.
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