Limits of the human-PBL-SCID mice model: severe restriction of the V beta T-cell repertoire of engrafted human T cells.
A recent study in the human-peripheral blood lymphocytes severe combined immunodeficiency (hu-PBL-SCID) model, analyzing the specificity of the engrafted human T cells, showed that human T-cell lines and clones derived from engrafted cells presented a xenoreactivity toward murine host molecules. This observation raised the question of the influence of the SCID environment on the ex vivo repertoire and function on the human T cells reconstituting the murine host. We have characterized the human V beta repertoire in the spleen of hu-PBL-SCID mice 1 to 3 months after their engraftment. Fluorescence-activated cell sorting (FACS) analysis of human V beta T-cell representation showed that, for all chimeras, all tested V beta subsets were submitted to underrepresentation and/or expansion upon engraftment. Importantly, these quantitative modifications of the T-cell repertoire were associated with a severe restriction in both the CDR3 size distribution pattern of the V beta transcripts and the number of J beta segments used by these transcripts. In addition, ex vivo phenotypic characterization of engrafted cells showed that 70% to 100% expressed the activation markers HLA-DR, CD45RO, and CD38. Taken together, these results suggest that, following their engraftment, human T cells were submitted to a massive antigenic selection. Moreover, we found that these activated T cells were unresponsive to in vitro mitogenic and superantigenic activation. The consequences of the skewed repertoire and altered function of engrafted human T cells on the validity of this humanized murine model are discussed.
Garcia
S
S
Département SIDA et Rétrovirus, Institut Pasteur, Paris, France.
Dadaglio
G
G
Gougeon
M L
ML
D000818:Animals; D017209:Apoptosis; D002469:Cell Separation; D002678:Chimera; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006085:Graft Survival; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D012641:Selection, Genetic; D013045:Species Specificity; D013154:Spleen / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000473:pathology* / Q000637:transplantation; D014183:Transplantation, Heterologous / Q000473:pathology*
D016693:Receptors, Antigen, T-Cell, alpha-beta