B7-H4-deficient mice display augmented neutrophil-mediated innate immunity.
B7-H4 is an immunoglobulin superfamily molecule and shown to be inhibitory for T-cell responses. To explore physiologic roles of B7-H4, we created B7-H4-deficient (KO) mice by genetic targeting. B7-H4KO mice are healthy and their T- and B-cell responses to polyclonal antigens are in normal range. However, B7-H4KO mice are more resistant to infection by Listeria monocytogenes than their littermates. Within 3 days after infection, bacterial colonies in livers and spleens are significantly lower than the controls, suggesting a role of B7-H4 in enhancing innate immunity. Further studies demonstrate that neutrophils increase in peripheral organs of B7-H4KO mice more so than their littermates but their bactericidal functions remain unchanged. Augmented innate resistance is completely dependent on neutrophils, even in the absence of adaptive immunity. In vitro B7-H4 inhibits the growth of bone marrow-derived neutrophil progenitors, suggesting an inhibitory function of B7-H4 in neutrophil expansion. Our results identify B7-H4 as a negative regulator of the neutrophil response to infection and provide a new target for manipulation of innate immunity.
Zhu
Gefeng
G
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Augustine
Mathew M
MM
Azuma
Takeshi
T
Luo
Liqun
L
Yao
Sheng
S
Anand
Sudarshan
S
Rietz
A Cecilia
AC
Huang
Jiaqiang
J
Xu
Haiying
H
Flies
Andrew S
AS
Flies
Sarah J
SJ
Tamada
Koji
K
Colonna
Marco
M
van Deursen
Jan M A
JM
Chen
Lieping
L
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000382:microbiology; D018122:B7-1 Antigen / Q000235:genetics* / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology; D039481:CD11b Antigen / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D008088:Listeriosis / Q000276:immunology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000382:microbiology; D010587:Phagocytosis / Q000276:immunology; D019707:Receptors, Chemokine / Q000378:metabolism; D016897:Respiratory Burst / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1
D018122:B7-1 Antigen; D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse