Regulation of human cell engraftment and development of EBV-related lymphoproliferative disorders in Hu-PBL-scid mice

Human PBMC engraft in mice homozygous for the severe combined immunodeficiency (Prkdc(scid)) mutation (Hu-PBL-scid mice), Hu-PBL-NOD-scid mice generate 5- to 10-fold higher levels of human cells than do Hu-PBL-C.B-17-scid mice, and Hu-PBL-NOD-scid beta(2)-microglobulin-null (NOD-scid-B2m(null)) mice support even higher levels of engraftment, particularly CD4(+) T cells. The basis for increased engraftment of human PBMC and the functional capabilities of these cells in NOD-scid and NOD-scid-B2m(null) mice are unknown, We now report that human cell proliferation in NOD-scid mice increased after in vivo depletion of NK cells. Human cell engraftment depended on CD4(+) cells and required CD40-CD154 interaction, but engrafted CD4(+) cells rapidly became nonresponsive to anti-CD3 Ab stimulation. Depletion of human CD8(+) cells fed to increased human CD4(+) and CD20(+) cell engraftment and increased levels of human Ig, We further document that Hu-PBL-NOD-scid mice are resistant to development of human EBV-related lymphoproliferative disorders, These disorders, however, develop rapidly following depletion of human CD8(+) cells and are prevented by re-engraftment of CD8(+) T cells. These data demonstrate that 1) murine NK cells regulate human cell engraftment in acid recipients; 2) human CD4(+) cells are required for human CD8(+) cell engraftment; and 3) once engrafted, human CD8+ cells regulate human CD4(+) and CD20(+) cell expansion, Ig levels, and outgrowth of EBV-related lymphoproliferative disorders. We propose that the Hu-PBL-NOD-scid model is suitable for the in vivo analysis of immunoregulatory interactions between human CD4(+) and CD8(+) cells.