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

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

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 3

Variability and skewing of NP205 -specific T cells dependent on private specificity after heterologous infection.

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Variability and skewing of NP205 -s...
(A) TCR Vβ repertoire of PV NP205 tetramer–positive cells of 2 PV-immune mice 8 days after LCMV challenge (PV+LCMV). (B and C) Double-tetramer staining and TCR Vβ5.1,5.2 analysis. (B) Splenocytes from day 8 PV-infected LCMV-immune mice (LCMV+PV) stained with CD8 and tetramers. Numbers in upper-right corners represent the percentage of gated CD8 T cells binding LCMV NP205 and PV NP205 tetramers; representative of 3 experiments. (C) Histograms of Vβ5.1,5.2-positive cells after gating on CD8 and double tetramer–positive cells. (D and E) Private specificity of NP205 response. Splenocytes from individual LCMV-immune donor mice were transferred into 3 congenic recipients. (D) Numbers in upper-right corners represent the percentage of gated CD8 T cells binding both tetramers 8 days after PV infection. (E) TCR Vβ repertoire of LCMV NP205-specific CD8 T cells in LCMV-immune mice before and 8 days after PV infection. Percentage of Vβ usage was calculated after gating on the IFN-γ–positive CD8 T cell population. The percentage for other Vβ was calculated by subtracting the sum of the indicated Vβ families from 100%. Numbers in lower bar graphs represent mean percent of Vβ5.1,5.2 usage (A versus B: P < 0.005; A versus C: P < 0.0002; B versus C: P < 0.03). In B and C, letters A–J represent individual mice. In D, letters A–C represent donor mice, and numbers 1–3 represent recipient mice receiving cells from the specified donor.