Characterization of human lung immune cells in the humanized BRGSF mouse model

Highly immunodeficient BRGSF mice have proven to be suitable for reconstitution with human cord blood cell-derived CD34+ hematopoietic stem cells, enabling the generation of human immune system (HIS) mice. Here, we employ a robust comparative approach utilizing human lung biopsies to characterize the immunological landscape of the lung in BRGSF-HIS mice. Although only macrophages of mouse origin are detected in the alveoli, immunophenotyping of the lung interstitium reveals the presence of human natural killer cells and various T-cell subsets, including CD4+ and CD8+ T cells, γδ T cells, and regulatory T cells, at percentages comparable to those observed in human lungs. Monocytes and dendritic cells predominate within the human myeloid compartment, while neutrophils are underrepresented. Nevertheless, the injection of exogenous human granulocyte colony-stimulating factor promotes the egress of human CD15+ cells, primarily consisting of mature neutrophils. Interestingly, human T cells from BRGSF-HIS mice are responsive to CD3-mediated stimulation, and monocyte-derived macrophages exhibit remarkable in vitro plasticity in M1/M2-like polarization. In adherent myeloid cells from BRGSF-HIS mouse lungs, LPS challenges elicit the secretion of human cytokines, including IL-6, CCL17, IL-10, and IL-1RA, confirming the ability of human myeloid cells to mount inflammatory responses. These findings demonstrate that BRGSF-HIS mice possess human myeloid and lymphoid cell compartments in the lung interstitium comparable to humans. Although some limitations should be considered to ensure the suitability of HIS mice for specific research contexts, BRGSF-HIS mice provide valuable insights for studying immune mechanisms in certain human lung diseases.