Lack of prominent peptide–major histocompatibility complex features limits repertoire diversity in virus-specific CD8+ T cell populations

Abstract

Using both 'reverse genetics' and structural analysis, we have examined the in vivo relationship between antigenicity and T cell receptor (TCR) repertoire diversity. Influenza A virus infection of C57BL/6 mice induces profoundly different TCR repertoires specific for the nucleoprotein peptide of amino acids 366–374 (NP366) and the acid polymerase peptide of amino acids 224–233 (PA224) presented by H-2Db. Here we show the H-2Db–NP366 complex with a 'featureless' structure selected a limited TCR repertoire characterized by 'public' TCR usage. In contrast, the prominent H-2Db–PA224 complex selected diverse, individually 'private' TCR repertoires. Substitution of the arginine at position 7 of PA224 with an alanine reduced the accessible side chains of the epitope. Infection with an engineered virus containing a mutation at the site encoding the exposed arginine at position 7 of PA224 selected a restricted TCR repertoire similar in diversity to that of the H-2Db–NP366–specific response. Thus, the lack of prominent features in an antigenic complex of peptide and major histocompatibility complex class I is associated with a diminished spectrum of TCR usage.

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Figure 1: The DbPA224 presents more dominant solvent-exposed features than the DbNP366 complex.
Figure 2: Infection of mice with mutant viruses containing single alanine substitutions in DbPA224 elicits epitope-specific CTL responses.
Figure 3: DbPA-R7A-specific CTLs show an altered TCR Vβ-region bias.
Figure 4: Loss of the dominant P7-Arg from PA224 results in altered TCR repertoire selection and more-limited repertoire diversity.
Figure 5: DbPA-R7A-specific CTLs show lower TCR avidity for pMHC than do DbPA224-specific CTLs.

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Acknowledgements

The authors thank J. Stambas for critical review of this manuscript, and D. Stockwell and Y. Sims for technical assistance. Supported by a Burnet Fellowship (P.C.D.) and a Peter Doherty Postdoctoral fellowship (K.K) from the Australian National Health and Medical Research Council, a Wellcome Trust Senior Research Fellowship (J.R.), Science, Technology and Innovation (Government of Victoria, Australia), Australian Research Council, National Health and Medical Research Council, Juvenile Diabetes Research Foundation, United States Public Health Service (AI29579) and American Lebanese Syrian Associated Charities at St. Jude Children's Research Hospital.

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Correspondence to Stephen J Turner.

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Supplementary information

Supplementary Fig. 1

Lung viral titers of mice infected with either HKx31 or PA-R7 viruses. (PDF 50 kb)

Supplementary Fig. 2

Narrowing of PA-R7A TCR repertoire diversity after secondary challenge. (PDF 51 kb)

Supplementary Fig. 3

Primer sequences. (PDF 46 kb)

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Turner, S., Kedzierska, K., Komodromou, H. et al. Lack of prominent peptide–major histocompatibility complex features limits repertoire diversity in virus-specific CD8+ T cell populations. Nat Immunol 6, 382–389 (2005). https://doi.org/10.1038/ni1175

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