Virus-Induced Maturation and Activation of Autoreactive Memory B Cells

Abstract

We have examined B cell populations that participate in distinct phases of the immune response to the influenza virus A/PR/8/34 hemagglutinin (HA) for their susceptibility to negative selection in mice that express the HA as a neo–self-antigen (HA104 mice). We demonstrated previously that specificity for the neo–self-HA causes a population of immunoglobulin G antibody-secreting cells, which dominate the primary response to virus immunization in BALB/c mice, to be negatively selected in HA104 mice. We find here that in contrast to these primary response B cells, HA-specific memory response B cells developed equivalently in HA104 and nontransgenic (BALB/c) mice. Indeed, there was no indication that HA-specific B cells were negatively selected during memory formation in influenza virus–immunized HA104 mice, even though the neo–self-HA can be recognized by memory B cells. Furthermore, HA-specific autoantibodies were induced in the absence of virus immunization by mating HA104 mice with mice transgenic for a CD4+ HA-specific T cell receptor. These findings indicate that specificity for a self-antigen does not prevent the maturation of autoreactive B cells in the germinal center pathway. Rather, the availability of CD4+ T cell help may play a crucial role in regulating autoantibody responses to the HA in HA104 mice.

Spontaneous Autoreactive Memory B Cell Formation Driven by a High Frequency of Autoreactive CD4+ T Cells

“…1D). Thus, PevHA mice resemble HA104 mice in which PR8 HA-specific memory B cell responses of virus-immunized mice are subjected to little or no negative selection by the self-PR8 HA molecule (30), and contrast HACII mice in which HA-specific B cells are negatively selected during memory formation (19).…”

“…By contrast, several hybridomas from PevHA mice used the C4 clonotype, identified by the use of the prototypic VC4/J5 gene segment combination, which participates in both primary and memory B cell responses in non-Tg mice ( Fig. 1C) (30,41). It was notable that three of the four hybridomas using the C4 clonotype secreted IgG Abs rather than the IgM Abs that are typically obtained after primary immunization of non-Tg mice, suggesting that C4 B cells in PevHA mice may have been preactivated by interactions with the self-HA molecule.…”

“…However, a separate population of B cells that participates in both primary and memory responses of virus-immunized BALB/c mice persists in HA Tg mice, and can be activated to generate primary Ab responses by virus immunization (19,29). Interestingly, the subsequent fate of these autoreactive HA-specific B cells can differ dramatically in different HA Tg lineages; in HA104 mice (which express HA driven by an SV40 promoter/enhancer), memory responses to secondary virus immunization were comparable to those of BALB/c mice, indicating that PR8 HA-specific B cells could undergo memory formation despite overt autoreactivity (30). By contrast, PR8 HA-specific B cells were subjected to negative selection during memory formation in HACII mice, which express high levels of PR8 HA driven by an MHC class II promoter, including by B cells themselves (19).…”

The Influence of Effector T Cells and Fas Ligand on Lupus-Associated B Cells

“…A total of 5-10 ϫ 10 6 Th1-or Th2-deviated CD4 ϩ cells from in vitro cultures were suspended in sterile PBS with 1000 hemagglutinating units (43) of purified PR8 influenza virus (15) and injected i.v.…”

“…Mice engineered to express the neoself Ag hemagglutinin (HA) on MHC class II-bearing cells (including B cells) were mated to V H 3H9 Ig Tg mice (14,15). Anti-HA CD4 ϩ T cells from TCR Tg mice and HA-expressing antichromatin B cells were then transferred together into a third-party recipient mouse and their fates tracked (16,17).…”