Pulmonary human immune responses in a humanized immune mouse model during influenza virus infection

Human immune system is complex and differs significantly from that of model animals. To study the human immune system, particularly the local mucosal immune cells responding to infectious diseases, the humanized mouse model is a powerful tool. In this study, we established a humanized immune system (HIS) mouse model by transplanting CD34⁺ hematopoietic stem cells from human umbilical cord blood into hIL7/hIL15 NDG mice. We successfully developed conventional human immune cells, including T cells, B cells, NK cells, monocytes, DCs and resident innate lymphoid cells (ILCs) in HIS mice. Following influenza A virus (IAV) infection, human pulmonary immune cells were activated and accumulated in the lungs. Single-cell sequencing data revealed that these immune cells functioned effectively in defending against viral infection by expressing cytotoxic cytokines and upregulating interferon-induced genes (ISGs). Furthermore, we identified human-specific genes that participated in regulating mucosal immune responses. Overall, hIL7/hIL15 HIS mice provide a useful model for studying human local immune responses against IAV in vivo.