Abstract
Humanized mice are expected to be useful as small animal models for in vivo studies on the pathogenesis of infectious diseases. However, it is well known that human CD8+ T cells cannot differentiate into effector cells in immunodeficient mice transplanted with only human CD34+ hematopoietic stem cells (HSCs), because human T cells are not educated by HLA in the mouse thymus. We here established HLA-B*51:01 transgenic humanized mice by transplanting human CD34+ HSCs into HLA-B*51:01 transgenic NOD/SCID/Jak3−/− mice (hNOK/B51Tg mice) and investigated whether human effector CD8+ T cells would be elicited in the mice or in those infected with HIV-1 NL4-3. There were no differences in the frequency of late effector memory and effector subsets (CD27lowCD28−CD45RA+/−CCR7− and CD27−CD28−CD45RA+/−CCR7−, respectively) among human CD8+ T cells and in that of human CD8+ T cells expressing CX3CR1 and/or CXCR1 between hNOK/B51Tg and hNOK mice. In contrast, the frequency of late effector memory and effector CD8+ T cell subsets and of those expressing CX3CR1 and/or CXCR1 was significantly higher in HIV-1-infected hNOK/B51Tg mice than in uninfected ones, whereas there was no difference in that of these subsets between HIV-1-infected and uninfected hNOK mice. These results suggest that hNOK/B51Tg mice had CD8+ T cells that were capable of differentiating into effector T cells after viral antigen stimulation and had a greater ability to elicit effector CD8+ T cells than hNOK ones.
Highlights
Humanized mice established by transplanting human CD34+ hematopoietic stem cells (HSCs) into immunodeficient mice would be a useful tool for in vivo studies of human immune responses, infectious diseases, preclinical testing of vaccines, and new therapeutic strategies
An earlier study of ours demonstrated that human CD8+ T cells from NOD/SCID/Jak32/2 mice transplanted with human CD34+ HSCs express perforin and granzyme B at a low level and fail to produce IFN-c and to proliferate after stimulation with alloantigens [16], suggesting that these human CD8+ T cells can not differentiate into effector cells in such mice. These results indicate that the effector function and antigen-specific responses of human CD8+ T cells could not be elicited in immunodeficient mice transplanted with only human CD34+ HSCs, because the reconstituted human CD8+ T cells were educated by mouse MHC-peptide complexes in the host thymus
The human T cells were maintained in the mice at least for 20 weeks after the transplantation, and transgenic expression of HLA-B51 did not influence the proportion of human T cells in hNOK/B51Tg mice compared with that in hNOK mice (Figure 1E, uninfected hNOK/B51Tg mouse, Figure S2A, uninfected hNOK mouse)
Summary
Humanized mice established by transplanting human CD34+ hematopoietic stem cells (HSCs) into immunodeficient mice would be a useful tool for in vivo studies of human immune responses, infectious diseases, preclinical testing of vaccines, and new therapeutic strategies. NOD/SCID/IL2rccnull (NOG) [1,2,3,4,5], NOD/SCID/IL2rcnull (NSG) [6,7] and Rag22/2cC2/2 mice [8] have been used as good recipients for human cell reconstitution [9,10,11]. The proliferation and IFN-c expression of Epstein-Barr virus (EBV)specific human CD8+ T cells have been demonstrated in humanized NOG, NSG, and Rag22/2cC2/2 mice established by transplanting human CD34+ HSCs into those mice after an EBV infection [8,13,14]. High-dose injection of EBV causes a fatal lymphoproliferative disorder in humanized NOG mice, whereas a lower-dose injection induces an apparently asymptomatic persistent infection [14], suggesting that the human
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