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
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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 8

Computer simulation of homologous versus heterologous virus challenge.

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Computer simulation of homologous versus ...
(A) Left: Clonal distribution of the memory population before (white bars) and after (black bars) a homologous challenge. Right: The same population before (white bars) and after (gray bars) a heterologous challenge. The x axis shows the absolute number of CD8 T cells, while y axis labels indicate hexadecimal representation of each clone involved in the response. Number in brackets on the left of the clone labels represents the place occupied by a particular clone in the immune hierarchy at the end of the primary response. Clones generated after the primary response are ordered according to decreasing cell number. This order is upset when there is a change of hierarchy occurring after the second challenge. rn, random number. (B) Computer simulation of effects of affinity on heterologous virus challenge–induced skewing of the T cell repertoire. Graphs show 2 examples of heterologous challenge in mice selected to possess a memory population with a defined percentage of high/low-affinity cells specific for the challenging virus (10% high/90% low in the left graph, 50% high/50% low in the right graph). White bars represent the memory population after the primary response and before the challenge, while gray bars represent the same population after the heterologous challenge. The x axis shows the size of each clone in terms of absolute cell number. On the y axis labels indicate the affinity of each clone for the heterologous virus: H, high affinity; M, medium affinity; L, low affinity; N, non–cross-reacting (see Methods).