Limits of the human-PBL-SCID mice model: Severe restriction of the Vβ T-cell repertoire of engrafted human T cells

Abstract

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 Vβ repertoire in the spleen of hu-PBL-SCID mice 1 to 3 months after their engraftment. Fluorescence- activated cell sorting (FACS) analysis of human Vβ T-cell representation showed that, for all chimeras, all tested Vβ 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 Vβ transcripts and the number of Jβ 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.