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^highCD28⁺CD45RA⁺+CCR7⁺, CD27⁺CD28⁺+CD45R^-A2CCR7⁺, 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^lowGraA⁺GraB⁺. These CD8⁺ T cells failed to produce IFN-γ 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.