Human Delta Like 1-Expressing Human Mesenchymal Stem Cells Promote Human T Cell Development and Antigen-Specific Response in Humanized NOD/SCID/IL-2Rgnull (NSG) Mice

Abstract Human delta-like 1 (hDlk1) is known to be able to regulate cell fate decisions duringhematopoiesis. Mesenchymal stem cells (MSCs) are known to exhibit potentimmunomodulatory roles in a variety of diseases. Herein, we investigated in vivofunctions of hDlkl1-hMSCs and hDlk1+hMSCs in T cell development and T cell responseto viral infection in humanized NOD/SCID/IL-2Rγnull (NSG) mice. Co-injection ofhDlk1-hMSC with hCD34+ cord blood (CB) cells into the liver of NSG mice markedlysuppressed the development of human T cells. In contrast, co-injection of hDlk1+hMSCwith hCD34+ CB cells into the liver of NSG dramatically promoted the development ofhuman T cells. Human T cells developed in humanized NSG mice represent markedlydiverse in terms of TCR Vβ usages, functionally active, and the restriction to human MHCmolecules. Upon challenge with Epstein-Barr virus (EBV), EBV-specific hCD8+ T cellsin humanized NSG mic were effectively mounted with phenotypically activated T cellspresented as hCD45+hCD3+hCD8+hCD45RO+hHLA-DR+ T cells, suggesting thatantigen-specific T cell response was induced in the humanized NSG mice. Taken together,our data suggest that the hDlk1-expressing MSCs can effectively promote thedevelopment of human T cells and immune response to exogenous antigen in humanizedNSG mice. Thus, the humanized NSG model might have potential advantages for thedevelopment of therapeutics targeting infectious diseases in the future.