Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 42, Issue 3, Pages 760-770Publisher
WILEY
DOI: 10.1002/eji.201141798
Keywords
Humanized mice; ISEApeaks; Multivariate score; T-cell repertoire; V-J rearrangements
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Funding
- DIM-Stem Pole of the Region Ile-de-France
- Agence Nationale de la Recherche (ANR)
- Association Francaise contre les Myopathies (AFM)
- Agence Nationale de la Recherche contre le SIDA (ANRS)
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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 beta chain of the T-cell receptor (hTRBV) in NOD.SCID.?c-/- (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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