Severely immunodeficient mouse strains, such as NOD.Cg-Prkdcscid Il2rg-/-, have been widely used to evaluate human immune responses, including applications in immuno-oncology in recent years. However, when human peripheral blood mononuclear cells (PBMCs) are engrafted in these mice, severe acute xenogeneic graft versus host disease (GvHD) arises due to engagement of human T cell receptors (TCRs) and murine major histocompatibility complex (MHC) I and II. GvHD shortens animal life span and results in only a brief window of evaluation of human immune cell functions in such mouse models. Efforts have been undertaken to reduce human PBMC-induced GvHD and to subsequently extend the window of human immunity assessment by eliminating mouse MHC I and MHC II (ref 1-3).