Failure of Effector Function of Human CD8+ T Cells in NOD/SCID/JAK3-/- Immunodeficient Mice Transplanted with Human CD34+ Hematopoietic Stem Cells

Humanized mice, which are generated by transplanting human CD34(+) hematopoietic stem cells into immunodeficient mice, are expected to be useful for the research on human immune responses. It is reported that antigen-specific T cell responses occur in immunodeficient mice transplanted with both human fetal thymus/liver tissues and CD34(+) fetal cells, but it remains unclear whether antigen-specific T cell responses occur in those transplanted with only human CD34(+) hematopoietic stem cells (HSCs). Here we investigated the differentiation and function of human CD8(+) T cells reconstituted in NOD/SCID/Jak3(-/-) mice transplanted with human CD34(+) HSCs (hNOK mice). Multicolor flow cytometric analysis demonstrated that human CD8(+) T cells generated from the CD34(+) HSCs comprised only 3 subtypes, i.e., CD27(high)CD28(+)CD45RA(+)CCR7(+), CD27(+)CD28(+)CD45RA(-)CCR7(+), and CD27(+)CD28(+)CD45RA(-)CCR7(-) and had 3 phenotypes for 3 lytic molecules, i.e., perforin(Per)(-)granzymeA(GraA)(-)granzymeB(GraB)(-), Per(-)GraA(+)GraB(-), and Per(low)GraA(+)GraB(+). These CD8(+) T cells failed to produce IFN-gamma and to proliferate after stimulation with alloantigens. These results indicate that the antigen-specific T cell response cannot be elicited in mice transplanted with only human CD34(+) HSCs, because the T cells fail to develop normally in such mice.