Half of the T-cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

Authors

  • Hang-Phuong Pham,

    1. Hôpital La Pitié-Salpêtrière, UPMC Univ Paris 06, UMR 7211, Paris, France
    2. Hôpital La Pitié-Salpêtrière, Centre National de la Recherche Scientifique CNRS, UMR 7211, Paris, France
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  • Manuarii Manuel,

    1. ImmunID Tech. CEA/iRTSSV, Grenoble, France
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  • Nicolas Petit,

    1. Hôpital La Pitié-Salpêtrière, UPMC Univ Paris 06, UMR 7211, Paris, France
    2. Hôpital La Pitié-Salpêtrière, Centre National de la Recherche Scientifique CNRS, UMR 7211, Paris, France
    3. INSERM, U959, Hôpital La Pitié-Salpêtrière Paris, France
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  • David Klatzmann,

    1. Hôpital La Pitié-Salpêtrière, UPMC Univ Paris 06, UMR 7211, Paris, France
    2. Hôpital La Pitié-Salpêtrière, Centre National de la Recherche Scientifique CNRS, UMR 7211, Paris, France
    3. INSERM, U959, Hôpital La Pitié-Salpêtrière Paris, France
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  • Sylvia Cohen-Kaminsky,

    1. INSERM UMR S-999, LabEx LERMIT, Hôpital Marie Lannelongue, Le Plessis Robinson, France
    2. Université Paris Sud, Faculté de Médecine Kremlin Bicêtre, Orsay, France
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  • Adrien Six,

    1. Hôpital La Pitié-Salpêtrière, UPMC Univ Paris 06, UMR 7211, Paris, France
    2. Hôpital La Pitié-Salpêtrière, Centre National de la Recherche Scientifique CNRS, UMR 7211, Paris, France
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  • Gilles Marodon

    Corresponding author
    1. Hôpital La Pitié-Salpêtrière, UPMC Univ Paris 06, UMR 7211, Paris, France
    2. Hôpital La Pitié-Salpêtrière, Centre National de la Recherche Scientifique CNRS, UMR 7211, Paris, France
    3. INSERM, U959, Hôpital La Pitié-Salpêtrière Paris, France
    • UPMC CNRS UMR7211, 83 Bd de l'Hôpital, Bât CERVI, 75013 PARIS, France, Fax: 133-14-217-7462
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Abstract

In humanized mice, the T-cell repertoire is derived from genetically identical human progenitors in distinct animals. Thus, careful comparison of the T-cell repertoires of humanized mice with those of humans may reveal the contribution of genetic determinism on T-cell repertoire formation. Here, we performed a comprehensive assessment of the distribution of V-J combinations of the human β chain of the T-cell receptor (hTRBV) in NOD.SCID.γc−/− (NSG) humanized mice. We observed that numerous V-J combinations were equally distributed in the thymus and in the periphery of humanized mice compared with human references. A global analysis of the data, comparing repertoire perturbation indices in humanized NSG mice and unrelated human PBMCs, reveals that 50% of the hTRBV families significantly overlapped. Using multivariate ranking and bootstrap analyses, we found that 18% of all possible V-J combinations contributed close to 50% of the expressed diversity, with significant over-representation of BV5-J1.1+1.2 and BV6-J1.1+1.2 rearrangements. Finally, comparison of CD3 and CD3+ thymocyte repertoires indicated that the observed V-J combination overlap was already present before TCR-MHC selection in the thymus. Altogether, our results show that half of the T-cell repertoire combinatorial diversity in humans is genetically determined.

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