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Narrowed TCR repertoire and viral escape as a consequence of heterologous immunity
Markus Cornberg, … , Raymond M. Welsh, Liisa K. Selin
Markus Cornberg, … , Raymond M. Welsh, Liisa K. Selin
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1443-1456. https://doi.org/10.1172/JCI27804.
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Research Article Immunology Article has an altmetric score of 3

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

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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 cross-reactivity. 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.

Authors

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

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Figure 5

A subset of LCMV NP205 –specific clones is expanded after heterologous PV infection.

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                  A subset of LCMV NP205
                  –specific cl...
PBMCs were from 2 LCMV-immune mice before and 8 days after PV infection. (A and C) LCMV NP205 tetramer–positive CD8 T cells were sorted, and Vβ mRNA expression was analyzed by RT-PCR with specific primers for Vβ1–18. (B, D, and E) The PCR products from dominant Vβ16 (M1, A and B; M2, D) and from Vβ 5.1 (M2, D) were subcloned, and 13–32 clones were sequenced per group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
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