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Induction of B cell tolerance or activation was analyzed with vesicular stomatitis virus (VSV) glycoprotein (G) expressed as a neo-self Ag. A membrane form of VSV-G expressed in all tissues, including the bone marrow, induced unresponsiveness at both the Th and B cell level, whereas a soluble form of VSV-G expressed peripherally in liver and kidney did not tolerize B cells and only reversibly anergized Th cells. Interestingly, a similar correlation was found for activation of mature lymphocytes. When mature normal spleen cells were transferred into the two transgenic mouse lines, the membrane form of VSV-G was strongly immunogenic for both Th and B cells, and high VSV-G-specific IgG Ab titers were induced in these transgenic mice. In contrast, spleen cells transferred into mice expressing the soluble form of VSV-G were not activated, and no VSV-G specific Abs were induced. These results indicate that highly immunogenic Ags are strongly tolerogenic for both immature B and T cells.

This study investigated whether or not the localization of persisting Ag influenced the localization of memory B and/or of Ab-forming cells (AFC). As a model Ag, we used vesicular stomatitis virus, which does not measurably replicate extraneuronally in adult mice after peripheral infection. Our results show that memory B cells and AFC are induced at the site where Ag is present; induced memory B cells then recirculate throughout the lymphoid system independently of Ag localization. In contrast, AFC are induced only at the sites of Ag persistence. These triggered Ab producing cells do not recirculate through the lymphoid tissue but migrate to the bone marrow.

After infection with some viruses that tend to persist, neutralizing antibodies are generated rather late, i.e., after 1 to 3 mo. This has been observed for HIV, Hepatitis B infection in man, or after infection with lymphocytic choriomeningitis virus (LCMV) in mice. In contrast, nonneutralizing antibodies to LCMV are generated by day 7 and reach high titers by day 10. This study attempts to evaluate reasons for late and low titered neutralizing antibody responses. After a primary infection with low doses (10(2) plaque forming units) of the poorly cytopathic LCMV-WE, neutralizing antibodies were rarely produced at detectable levels before days 60 to 120. In vivo depletion of CD8+ CTL led to a marked enhancement and acceleration of kinetics of the neutralizing antibody response. In contrast, nonneutralizing antibodies, including those specific for LCMV-GP carrying the neutralizing determinant, were detectable very early, i.e., 4 to 7 days after infection, with maximum titers usually by day 10 irrespective of the presence or absence of CTL. Mice completely lacking CD8+ T cells because of deletion by homologous recombination (CD8-/-) also exhibited neutralizing antibodies early by day 10 to 20, and by day 120 reached very high titers. The neurotropic isolate LCMV-ARMSTRONG induced low but significant titers of neutralizing antibodies relatively early (i.e., by days 7 to 10), whereas the lympho-viscerotrope mutant virus LCMV-ARMSTRONG Cl-13 did not. Early and effective CTL responses causing immunopathology (and immunosuppression) correlated with the absence of neutralizing antibodies. The discrepancy between the CTL-dependent inhibition of neutralizing versus unimpaired anti-GP ELISA responses cannot be explained by different Ag doses alone. Additionally, it may reflect different kinetics of the responses, whereby the later neutralizing responses possibly requiring IgG affinity maturation may be more susceptible to general immunosuppression; also B cells expressing neutralizing receptors, but not those with antibodies binding GP (or NP), may be actively infected, therefore they present viral peptides on class I MHC Ag and may become targets for anti-LCMV-specific CTL.