Human delta like 1-expressing human mesenchymal stromal cells promote human T cell development and antigen-specific response in humanized NOD/SCID/IL-2Rγnull (NSG) mice

Human delta-like 1 (hDlk1) is known to be able to regulate cell fate decisions during hematopoiesis. Mesenchymal stromal cells (MSCs) are known to exhibit potent immunomodulatory roles in a variety of diseases. Herein, we investigated in vivo functions of hDlk1(-)hMSCs and hDlk1(+)hMSCs in T cell development and T cell response to viral infection in humanized NOD/SCID/IL-2R gamma (null) (NSG) mice. Co-injection of hDlk1(-)hMSC with hCD34(+) cord blood (CB) cells into the liver of NSG mice markedly suppressed the development of human T cells. In contrast, co-injection of hDlk1(+)hMSC with hCD34(+) CB cells into the liver of NSG dramatically promoted the development of human T cells. Human T cells developed in humanized NSG mice represent markedly diverse, functionally active, TCR V beta usages, and the restriction to human MHC molecules. Upon challenge with Epstein-Barr virus (EBV), EBV-specific hCD8(+) T cells in humanized NSG mice were effectively mounted with phenotypically activated T cells presented as hCD45(+)hCD3(+)hCD8(+)hCD45RO(+)hHLA-DR+ T cells, suggesting that antigen-specific T cell response was induced in the humanized NSG mice. Taken together, our data suggest that the hDlk1-expressing MSCs can effectively promote the development of human T cells and immune response to exogenous antigen in humanized NSG mice. Thus, the humanized NSG model might have potential advantages for the development of therapeutics targeting infectious diseases in the future.