Activation and negative selection of functionally distinct subsets of antibody-secreting cells by influenza hemagglutinin as a viral and a neo-self antigen

doi:10.1084/jem.183.1.13

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Activation and negative selection of functionally distinct subsets of antibody-secreting cells by influenza hemagglutinin as a viral and a neo-self antigen

AJ Caton, JR Swartzentruber, AL Kuhl, SR Carding and SE Stark
Wistar Institute, Philadelphia, Pennsylvania 19104, USA.

We have compared transgenic mice that express the influenza virus PR8 hemagglutinin (PR8 HA) as a membrane-bound neo-self antigen (HA104 mice) with nontransgenic (non-Tg) mice for their ability to generate HA- specific B cell responses after primary immunization with PR8 virus. HA- specific, IgM-secreting B cells were induced with similar frequencies in HA104 and non-Tg mice. In addition, a B cell clonotype (C4) that is characteristic of anti-HA immune responses of BALB/c mice was identified among HA-specific IgM hybridomas from HA104 mice. A subset of HA-specific, IgG-secreting B cells that arises rapidly after primary virus immunization in non-Tg mice, however, was substantially reduced in HA104 mice. Likewise, a B cell clonotype (C12) that dominates HA- specific IgG hybridomas generated after primary immunization of non-Tg mice was present at greatly reduced frequencies among hybridomas from HA104 mice. Because HA-specific, IgG-secreting B cells were generated by HA104 mice in response to a mutant HA containing an amino acid interchange in a B cell antigenic site, we conclude that these PR8 HA- specific, IgG-secreting B cells are negatively selected in HA104 mice as a result of their specificity for the neo-self PR8 HA. The findings demonstrate that HA-specific B cells that display distinct phenotypic potentials in non-Tg mice also differ in their susceptibility to negative selection from the primary B cell repertoire of HA104 mice: a subset of B cells that undergo rapid differentiation to become HA- specific IgG antibody-secreting cells (ASC) after activation in non-Tg mice is negatively selected in HA104 mice. By contrast, a subset that gives rise to HA-specific, IgM-secreting ASC persists in the primary repertoire of HA104 mice and can be activated by virus immunization.
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