Generation and characterization of B7-H4/B7S1/B7x-deficient mice.
Members of the B7 family of cosignaling molecules regulate T-cell proliferation and effector functions by engaging cognate receptors on T cells. In vitro and in vivo blockade experiments indicated that B7-H4 (also known as B7S1 or B7x) inhibits proliferation, cytokine production, and cytotoxicity of T cells. B7-H4 binds to an unknown receptor(s) that is expressed on activated T cells. However, whether B7-H4 plays nonredundant immune regulatory roles in vivo has not been tested. We generated B7-H4-deficient mice to investigate the roles of B7-H4 during various immune reactions. Consistent with its inhibitory function in vitro, B7-H4-deficient mice mounted mildly augmented T-helper 1 (Th1) responses and displayed slightly lowered parasite burdens upon Leishmania major infection compared to the wild-type mice. However, the lack of B7-H4 did not affect hypersensitive inflammatory responses in the airway or skin that are induced by either Th1 or Th2 cells. Likewise, B7-H4-deficient mice developed normal cytotoxic T-lymphocyte reactions against viral infection. Thus, B7-H4 plays a negative regulatory role in vivo but the impact of B7-H4 deficiency is minimal. These results suggest that B7-H4 is one of multiple negative cosignaling molecules that collectively provide a fine-tuning mechanism for T-cell-mediated immune responses.
Suh
Woong-Kyung
WK
Campbell Family Institute for Breast Cancer Research, 620 University Ave., Suite 706, Toronto, Ontario, Canada. woong-kyung.suh@ircm.qc.ca
Wang
Seng
S
Duncan
Gordon S
GS
Miyazaki
Yoshiyuki
Y
Cates
Elizabeth
E
Walker
Tina
T
Gajewska
Beata U
BU
Deenick
Elissa
E
Dawicki
Wojciech
W
Okada
Hitoshi
H
Wakeham
Andrew
A
Itie
Annick
A
Watts
Tania H
TH
Ohashi
Pamela S
PS
Jordana
Manel
M
Yoshida
Hiroki
H
Mak
Tak W
TW
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D018122:B7-1 Antigen / Q000378:metabolism*; D049109:Cell Proliferation; D018390:Gene Targeting; D007249:Inflammation / Q000276:immunology; D009980:Influenza A virus / Q000502:physiology; D018320:Leishmania major / Q000502:physiology; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000469:parasitology; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1
D018122:B7-1 Antigen; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse