Exploration of Human Lung-Resident Immunity and Response to Respiratory Viral Immunization in a Humanized Mouse Model

There are urgent needs for humanized mouse models of viral respiratory diseases to study immunopathogenesis and therapeutic interventions. Although human immune system (HIS) mice permit analysis in real time of human immune responses in vivo, evolutionary divergences preclude their usefulness for the respiratory viruses that do not infect mouse lungs. In this study, we sought to use HIS mice with human lung (HL) tissue xenografts (HISL mice) to address this issue. The grafted HL tissue maintained histologically normal structure, and populated with human tissue-resident immune cells, including CD11c⁺ dendritic cells and CD4⁺ and CD8⁺ tissue-resident memory T cells. HISL mice showed a marked expansion of tissue-resident memory T cells and generation of viral Ag-specific T cells in the HL xenografts, and production of antiviral IgM and IgG Abs upon immunization of the HL xenograft by H1N1 influenza viruses. RNA-seq analysis on H1N1-infected and control HL xenografts identified a total of 5089 differentially expressed genes with enrichments for genes involved in respiratory diseases, viral infections, and associated immune responses. Furthermore, prophylactic viral exposures resulted in protection against subsequent lethal challenge by intranasal viral inoculation. This study supports the usefulness of this preclinical model in exploring the immunopathology and therapies of respiratory viral diseases.