Efficient peripheral construction of functional human regulatory CD4 ⁺CD25 ^highFoxp3 ⁺ T cells in NOD/SCID mice grafted with fetal human thymus/liver tissues and CD34 ⁺ cells

Regulatory T cells, especially CD4 ⁺CD25 ⁺ regulatory T cells are critical regulators of immune tolerance in humans and mice. Mice with humanized immunity have been developed by various transplantation strategies of human tissues or cells related to immunity, which are being extensively applied in biomedical research. However, it is unclear whether human CD4 ⁺CD25 ⁺ regulatory T cells can normally develop in human thymic grafts and efficiently populate in the periphery in NOD/SCID mouse recipients. In human thymic grafts, high percentage of mature human CD4 ⁺CD25 ^high regulatory T cells was detected. Human CD4 ⁺CD25 ⁺ regulatory T cells maturing in fetal human thymus grafts could subsequently output to the periphery of NOD/SCID mouse recipients. Importantly, these cells exhibited Foxp3 ⁺CD45RO ⁺CTLA4 ⁺CD127 ^- phenotype, similarly to those in healthy individuals. In addition, human CD4 ⁺CD25 ⁺ regulatory T cells maturing in human thymic grafts suppressed proliferative response of CD4 ⁺CD25 ^- T cells to allogeneic antigens, though the peripheral CD4 ⁺CD25 ⁺ regulatory T cells in fetal human thymus-grafted NOD/SCID mice showed somewhat decreased immunosuppressive ability compared with normal CD4 ⁺CD25 ⁺ regulatory T cells. Thus, this humanized animal model is suitable for examining development and function of human CD4 ⁺CD25 ⁺ regulatory T cells in vivo.