title: Half of the T-cell repertoire combinatorial diversity is genetically determined in humans and humanized mice.
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.
authors: Hôpital La Pitié-Salpêtrière, UPMC Univ Paris 06, UMR 7211, Paris, France.
authors: Hang-Phuong
authors: HP
authors: Pham
authors: Manuarii
authors: M
authors: Manuel
authors: Nicolas
authors: N
authors: Petit
authors: David
authors: D
authors: Klatzmann
authors: Sylvia
authors: S
authors: Cohen-Kaminsky
authors: Adrien
authors: A
authors: Six
authors: Gilles
authors: G
authors: Marodon
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005434:Flow Cytometry; D015321:Gene Rearrangement / Q000235:genetics / Q000276:immunology; D006801:Humans; D007133:Immunoglobulin Joining Region / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D016014:Linear Models; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000276:immunology*; D060152:V(D)J Recombination / Q000235:genetics / Q000276:immunology
chemical_list: D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D011948:Receptors, Antigen, T-Cell; D004247:DNA