Antiviral immune responses in gene-targeted mice expressing the immunoglobulin heavy chain of virus-neutralizing antibodies

Abstract

Two gene-targeted immunoglobulin heavy chain transgenic mouse strains, TgH(KL25) and TgH(VI10), expressing neutralizing specificities for lymphocytic choriomeningitis virus and vesicular stomatitis virus, respectively, have been generated. Three days after lymphocytic choriomeningitis virus infection, TgH(KL25) mice showed a thymusindependent neutralizing IgM response followed by thymus-dependent (TD) IgG. In contrast, WT mice mounted only a TD IgG response around day 80. These observations indicated that not only structural properties of the virus but also immunological parameters such as the frequency of B cells were indicative for the induction of thymusindependent versus TD Ig responses. Naïve vesicular stomatitis virusspecific Ig heavy chain transgenic mice displayed greatly elevated natural antibody titers. However, despite these high naïve titers, de novo activation of naïve CD4 ؉ T and B cells was not blocked. Therefore, B cells giving rise to natural antibodies do not participate in virus-induced antibody responses.

Low-affinity B cells transport viral particles from the lung to the spleen to initiate antibody responses

“…We next addressed whether VLPs bound to B cells via BCR. To this end, we used (VI10)xYEN mice, which express a BCR specific for vesicular stomatitis virus (VSV) (38). These mice have a quasimonoclonal B-cell repertoire and are essentially only able to bind VSV glycoprotein.…”

Parameters governing exhaustion of rare T cell‐independent neutralizing IgM‐producing B cells after LCMV infection

“…The frequency of heavy chain transgenic antibody-forming cells (tghAFC) was quantified after adoptive transfer of 3 Â 10 7 TgH(KL25) splenocytes on day -1. ELIspot assays were performed using IgM-or IgG-specific capturing antibodies, followed by detection with IIIC4.8, an antibody specific for the heavy chain of KL25 [11]. As depicted in Fig.…”

“…At days 4, 7 and 11, splenocytes were stained intra-and extracellularly with IIIC4.8, an mAb recognizing the heavy chain of KL25, and B2.5, an mAb recognizing the combination of the KL25 heavy and light chains of the original KL25 antibody [11]. nAbproducing cells were identified by bright doublestaining with both anti-KL25 antibodies (Fig.…”

“…In this work, we have used the gene-targeted mouse strain TgH(KL25), expressing the heavy chain of the LCMV-neutralizing monoclonal antibody (mAb) KL25 [11]. In contrast to WT mice, TgH(KL25) mice mount a strong nAb response within 3-4 days following LCMV infection and rapidly control the virus.…”

“…In contrast to WT mice, TgH(KL25) mice mount a strong nAb response within 3-4 days following LCMV infection and rapidly control the virus. In these mice, the IgM response against LCMV is T cell independent [11]. The level of antigen to which the immune system is exposed over time has been identified as an important factor controlling CD8 + T cell responses [12].…”