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 combin ed 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 t he human V beta repertoire in the spleen of hu-PBL-SCID mice 1 to 3 mo nths after their engraftment. Fluorescence-activated cell sorting (FAG S) analysis of human V beta T-cell representation showed that for all chimeras, all tested V beta subsets were submitted to underrepresentat ion 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 t ranscripts 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, CD45R O, and CD38. Taken together, these results suggest that, following the ir engraftment, human T cells were submitted to a massive antigenic se lection. Moreover, we found that these activated T cells were unrespon sive to in vitro mitogenic and superantigenic activation. The conseque nces of the skewed repertoire and altered function of engrafted human T cells on the validity of this humanized murine model are discussed. (C) 1997 by The American Society of Hematology.