Time-dependent induction of protective anti-influenza immune responses in human peripheral blood lymphocyte/SCID mice.

The human (hu) PBL/SCID mouse model has the potential to provide a powerful tool for the study of human immune function. However, at peak engraftment (4-8 wk postinjection), recovered human T cells are largely unresponsive to foreign Ag and have converted to an activated/memory-type phenotype. Here we show that this conversion is not a prerequisite for engraftment because at early stages (2 wk) a substantial fraction of human T cells detected in SCID peripheral blood retains the unactivated/naive phenotype of donor PBL. This early stage is also associated with a TCR repertoire in both the CD4 and CD8 subsets that is similar to that in the donor. Importantly, we show that strong HLA class I allele- and peptide-specific cytotoxic T lymphocyte as well as humoral responses can be generated in this model when human cells encounter Ag (infection with influenza A) at early, but not late, stages in engraftment. This early human response was also functional, as partial protection against influenza-induced pathology and death in SCIDs was observed. Taken together, these results demonstrate that the huPBL/SCID model can support the generation of potent and specific CTL and humoral responses provided that Ag is introduced early, presumably before the time-dependent generalized xenoactivation of engrafted human cells.