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Deliberate removal of T cell help improves virus-neutralizing antibody production

Nature Immunology volume 5, pages 934–942 (2004)Cite this article

Abstract

The B cell response to lymphocytic choriomeningitis virus is characterized by a CD4+ T cell–dependent polyclonal hypergammaglobulinemia and delayed formation of virus-specific neutralizing antibodies. Here we provide evidence that, paradoxically, because of polyclonal B cell activation, virus-specific T cell help impairs the induction of neutralizing antibody responses. Experimental reduction in CD4+ T cell help in vivo resulted in potent neutralizing antibody responses without impairment of CD8+ T cell activity. These unexpected consequences of polyclonal B cell activation may affect vaccine strategies and the treatment of clinically relevant chronic bacterial, parasitic and viral infections in which hypergammaglobulinemia is regularly found.

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Figure 1: Influence of CD8+ T cells on B cell and CD4+ T cell responses.
Figure 2: Inverse correlation between virus-specific T cell help and neutralizing antibody responses in Cd8a−/− mice.
Figure 3: Infection with LCMV-WEdel results in moderate hypergammaglobulinemia but potent neutralizing antibody responses in immunocompetent C57BL/6 mice.
Figure 4: Enhanced neutralizing antibody response after partial CD4+ T cell depletion in vivo in both immunocompetent C57BL/6 and Cd8a−/− mice.
Figure 5: Normal early and memory CTL function can coexist with enhanced neutralizing antibody responses in immunocompetent C57BL/6 mice.
Figure 6: The efficiency of the neutralizing antibody response can be predicted largely by the extent of polyclonal B cell activation but is also modified by the extent of virus replication.
Figure 7: LCMV-induced polyclonal B cell competition acts in an antigen-nonspecific way and is dependent on B cell precursor frequency.

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Acknowledgements

We thank A.J. MacPherson and D. Pinschewer for discussions; E. Horvath, K. Tschannen and J. Weber for technical assistance; and the Institute of Clinical Chemistry, University Hospital Zürich, Switzerland for technical support. Supported by the European Union project (QLK-2000-01476) on combined immune and gene therapy of chronic hepatitis, the Swiss National Foundation, the Kanton of Zürich, Switzerland, Eidgenössische Technische Hochschule (Zürich, Switzerland) and Deutsche Forschungsgemeinschaft (LA1419/1-1 to K.S.L.).

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  1. Mike Recher, Karl S Lang and Lukas Hunziker: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Experimental Immunology, University Hospital Zürich, Schmelzbergstrasse 12, Zürich, CH-8091, Switzerland

    Mike Recher, Karl S Lang, Lukas Hunziker, Stefan Freigang, Bruno Eschli, Nicola L Harris, Alexander Navarini, Beatrice M Senn, Katja Fink, Marius Lötscher, Lars Hangartner, Raphaël Zellweger, Hans Hengartner & Rolf M Zinkernagel

  2. Department of Pneumology, University Hospital Basel, Petersgraben 4, Basel, 4021, Switzerland

    Lukas Hunziker

  3. Institute of Clinical Chemistry, University Hospital Zürich, Rämistrasse 100, Zürich, CH-8091, Switzerland

    Martin Hersberger

  4. University Hospital Basel, Experimental Hematology, Hebelstrasse 20, Basel, CH-4031, Switzerland

    Alexandre Theocharides

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Supplementary Fig. 1

Influence of viral dosage on CD4+ T cell function (PDF 42 kb)

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Recher, M., Lang, K., Hunziker, L. et al. Deliberate removal of T cell help improves virus-neutralizing antibody production. Nat Immunol 5, 934–942 (2004). https://doi.org/10.1038/ni1102

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