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Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes

Nature volume 394, pages 482–485 (1998)Cite this article

Abstract

Some viruses, including human immunodeficiency virus (HIV) and hepatitis B virus (HBV) in humans, and lymphocytic choriomeningitis virus (LCMV) in mice, are initially controlled by cytotoxic T lymphocytes (CTLs), but may subsequently escape through mutation of the relevant T-cell epitope1,2,3. Some of these mutations preserve the normal binding to major histocompatibility complex class I molecules, but present an altered surface to the T-cell antigen receptor4,5. The exact role of these so-called altered peptide ligands in vivo is not clear. Here we report that mice primed with LCMV-WE strain respond to a subsequent infection by WE-derived CTL epitope variants with a CTL response directed against the initial epitope rather than against the new variant epitope. This phenomenon of ‘original antigenic sin’ was initially described in influenza6,7,8 and is an asymmetric pattern of protective antibody crossreactivity determined by exposure to previously existing strains, which may therefore extend to some CTL responses. Original antigenic sin by CTL leads to impaired clearance of variant viruses infecting the same individual and so may enhance the immune escape of mutant viruses evolving in an individual host.

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Figure 1: CTL responses of C57BL/6 mice to a single or second virus infection.
Figure 2: Ex vivo responses of BALB/c mice to a single or second virus infection.
Figure 3: CTL responses to APLs in dominant and subdominant epitopes.
Figure 4: Evaluation of specific versus bystander restimulation in vivo.
Figure 5: Impaired clearance of LCMV epitope variants from primed mice.

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Acknowledgements

This work was sponsored by the Wellcome Trust, the Swiss National Foundation for Science and the Kanton of Zurich. We thank E. Horvath for technical work, and P. Aichele, M. Bachmann, S. Ehl and A. McPherson for discussion.

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  1. Institute for Experimental Immunology, University Hospital, Schmelzbergstrasse, 8091 12, Zurich, Switzerland

    Paul Klenerman & Rolf M. Zinkernagel

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Correspondence to Rolf M. Zinkernagel.

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Klenerman, P., Zinkernagel, R. Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 394, 482–485 (1998). https://doi.org/10.1038/28860

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