Failure of effector function of human CD8+ t cells in NOD/SCID/JAK3-/- immunodeficient mice transplanted with human CD34+ hematopoietic stem cells

Abstract

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., CD27highCD28+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 PerlowGraA+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. © 2010 Sato et al.