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Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice
Author(s) -
Pham HangPhuong,
Manuel Manuarii,
Petit Nicolas,
Klatzmann David,
CohenKaminsky Sylvia,
Six Adrien,
Marodon Gilles
Publication year - 2012
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.201141798
Subject(s) - biology , repertoire , humanized mouse , t cell receptor , cd8 , nod , t cell , complementarity determining region , genetics , computational biology , antibody , gene , antigen , immune system , immunoglobulin light chain , physics , acoustics
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.