Narrowed TCR repertoire and viral escape as a consequence of heterologous immunity

Markus Cornberg, Alex T. Chen, Lee A. Wilkinson, Michael A. Brehm, Sung Kwon Kim, Claudia Calcagno, Dario Ghersi, Roberto Puzone, Franco Celada, Raymond M. Welsh, Liisa K. Selin

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

Why some virus-specific CD8 TCR repertoires are diverse and others restricted or "oligoclonal" has been unknown. We show here that oligoclonality and extreme clonal dominance can be a consequence of T cell crossreactivity. Lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV) encode NP205-212 epitopes that induce different but highly cross-reactive diverse TCR repertoires. Homologous viral challenge of immune mice only slightly skewed the repertoire and enriched for predictable TCR motifs. However, heterologous viral challenge resulted in a narrow oligoclonal repertoire with dominant clones with unpredictable TCR sequences. This shift in clonal dominance varied with the private, i.e., unique, specificity of the host's TCR repertoire and was simulated using affinity-based computer models. The skewing differences in TCR repertoire following homologous versus heterologous challenge were observed within the same private immune system in mice adoptively reconstituted with memory CD8 T cell pools from the same donor. Conditions driving oligoclonality resulted in an LCMV epitope escape variant in vivo resembling the natural Lassa virus sequence. Thus, T cell oligoclonality, including extremes in clonal dominance, may be a consequence of heterologous immunity and lead to viral escape. This has implications for the design of peptide-based vaccines, which might unintentionally prime for skewed TCR responses to cross-reactive epitopes.

Original languageEnglish (US)
Pages (from-to)1443-1456
Number of pages14
JournalJournal of Clinical Investigation
Volume116
Issue number5
DOIs
StatePublished - May 1 2006

ASJC Scopus subject areas

  • Medicine(all)

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    Cornberg, M., Chen, A. T., Wilkinson, L. A., Brehm, M. A., Kim, S. K., Calcagno, C., Ghersi, D., Puzone, R., Celada, F., Welsh, R. M., & Selin, L. K. (2006). Narrowed TCR repertoire and viral escape as a consequence of heterologous immunity. Journal of Clinical Investigation, 116(5), 1443-1456. https://doi.org/10.1172/JCI27804