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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 7

Homologous versus heterologous infection of a private TCR repertoire.

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Homologous versus heterologous infection of a private TCR repertoire.
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Splenocytes from an LCMV-immune donor mouse were transferred into 2 congenic recipients. One recipient was infected with LCMV and the other was infected with PV. (A) TCR Vβ repertoire of NP205-specific CD8 T cells. Splenocytes from the LCMV-immune donor and recipient mice 8 days after LCMV or PV infection were stimulated with LCMV NP205 peptide. The percentage of Vβ usage was calculated on the gated IFN-γ–positive CD8 T cell population. Vβ17 served as a negative control. The percentage for other Vβ was calculated by subtracting the sum of the indicated Vβ families from 100%. C57BL/6-A, C57BL/6 donor A. (B) TCR Vβ 5.1,5.2 of LCMV NP205 tetramer–positive CD8 T cells before and after infection. Staining with LCMV NP205 tetramer and Vβ5.1,5.2 antibody was performed on the CD8 LCMV-immune or congenic donor CD8 T cells (LCMV+LCMV, LCMV+PV). The numbers shown above the gates represent the percentage of cells in the gate. The number in the upper-right quadrant (gray box) represents the percentage of LCMV NP205–specific CD8 T cells positive for Vβ5.1,5.2. This NP205-specific Vβ5.1,5.2 frequency was similar in the ICS assay. Data are from 1 of 5 experiments, where Vβ5.1,5.2 proliferated after PV infection. (C) Vβ clonotypes after PV or LCMV infection of mice harboring the same memory pool. Splenocytes from LCMV-immune mice were adoptively transferred into 2 recipient mice, which were then infected with LCMV or PV. This experiment used mice different from those represented in A and B.

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

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