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
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
View: Text | PDF | Corrigendum
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

×

Figure 2

Differences in the TCR Vβ repertoire of CD8 T cells specific to LCMV NP205 and PV NP205 .

Options: View larger image (or click on image) Download as PowerPoint
Differences in the TCR Vβ repertoire of CD8 T cells specific to LCMV NP...
(A) Splenocytes from day 8 LCMV- or PV-infected mice (n = 8) were stimulated with LCMV NP205, or PV NP205 peptides in an ICS assay and then stained with Vβ-specific mAbs. The percentage of Vβ usage was calculated after gating on the IFN-γ–positive CD8 T cell population. The percentage of other Vβ (Vβ15–18 were not included in the antibody pool) was calculated by subtracting the sum of Vβ2–14 from 100%. (B and C) TCR Vβ mRNA expression of LCMV NP205–specific CD8 T cells. LCMV NP205 tetramer–positive CD8 T cells were sorted from PBMCs 8 days after LCMV infection, and RNA was isolated. RT-PCR was performed with specific primers for Vβ1–18 (B). Spectratype analysis with specific primers for the indicated Vβ families (C). (D) The TCR Vβ16 repertoire of acute LCMV–infected mice is diverse. This shows the CDR3 amino acid sequence and the frequency of each unique Vβ16 LCMV NP205–sorted CD8 T cell clone represented in B. Clones with the same amino acid sequence that are plotted more than once have a different nucleic acid sequence. T cell clones with an XGGX-Jβ2.5 (QDTQY-F) motif dominate the response. (E) The TCR Vβ16 repertoire of acute PV–infected mice is diverse. (F) The TCR Vβ5.1 repertoire of acute PV–infected mice is diverse.