Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung.
Mice with a functional human immune system have the potential to allow in vivo studies of human infectious diseases and to enable vaccine testing. To this end, mice need to fully support the development of human immune cells, allow infection with human pathogens, and be capable of mounting effective human immune responses. A major limitation of humanized mice is the poor development and function of human myeloid cells and the absence of human immune responses at mucosal surfaces, such as the lung. To overcome this, we generated human IL-3/GM-CSF knock-in (hIL-3/GM-CSF KI) mice. These mice faithfully expressed human GM-CSF and IL-3 and developed pulmonary alveolar proteinosis because of elimination of mouse GM-CSF. We demonstrate that hIL-3/GM-CSF KI mice engrafted with human CD34(+) hematopoietic cells had improved human myeloid cell reconstitution in the lung. In particular, hIL-3/GM-CSF KI mice supported the development of human alveolar macrophages that partially rescued the pulmonary alveolar proteinosis syndrome. Moreover, human alveolar macrophages mounted correlates of a human innate immune response against influenza virus. The hIL-3/GM-CSF KI mice represent a unique mouse model that permits the study of human mucosal immune responses to lung pathogens.
Department of Immunobiology, The Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
Tim
T
Willinger
Anthony
A
Rongvaux
Hitoshi
H
Takizawa
George D
GD
Yancopoulos
David M
DM
Valenzuela
Andrew J
AJ
Murphy
Wojtek
W
Auerbach
Elizabeth E
EE
Eynon
Sean
S
Stevens
Markus G
MG
Manz
Richard A
RA
Flavell
D000818:Animals; D036101:Cord Blood Stem Cell Transplantation; D055879:Gene Knock-In Techniques; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal / Q000235:genetics; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007377:Interleukin-3 / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000821:virology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology*; D018183:Transplantation Chimera / Q000235:genetics / Q000276:immunology / Q000821:virology; D014183:Transplantation, Heterologous
C508596:IL3 protein, human; D007377:Interleukin-3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
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