Enhanced adaptive immunity in mice lacking the immunoinhibitory adaptor Hacs1.
Hacs1, a SH3 and SAM domain-containing adaptor protein, is up-regulated by IL-4 in activated B cells and strongly expressed in dendritic cells. To elucidate the function of Hacs1 in immune regulation, we generated Hacs1(-/-) mice by deletion of the SH3 and SAM domains. Hacs1(-/-) mice were viable and fertile and had normal bone marrow B-cell development and normal splenic T- and B-cell populations. However, adult Hacs1(-/-) mice had increased peritoneal B1a cells (IgM(+)CD5(+)). On immunization with T-cell-independent antigen TNP-Ficoll, Hacs1(-/-) mice had increased production of anti-TNP IgM and IgG3. Purified splenic B cells from Hacs1(-/-) mice showed increased cell proliferation on BCR (B-cell receptor) stimulation. We further demonstrate that the Hacs1(-/-) B cells had increased global tyrosine phosphorylation, including tyrosine kinases Lyn and Akt. Both T-helper type 1 (T(h)1) and T-helper type 2 (T(h)2) humoral responses were enhanced in Hacs1(-/-) mice. In vitro bone marrow-derived Hacs1(-/-) dendritic cells showed increased IL-12 production on stimulation with ovalbumin (OVA). This study suggests that Hacs1 is an immunoinhibitory adaptor that might be a useful target for immune suppression therapy.-Wang, D., Stewart, A. K., Zhuang, L., Zhu, Y., Wang, Y., Shi, C., Keating, A., Slutsky, A., Zhang, H., Wen, X.-Y. Enhanced adaptive immunity in mice lacking the immunoinhibitory adaptor Hacs1.
Wang
Dingyan
D
St. Michael's Hospital, 30 Bond St., Queen Wing, Rm 8-019, Toronto, ON, Canada M5B 1W8.
Stewart
A Keith
AK
Zhuang
Lihua
L
Zhu
Yuanxiao
Y
Wang
Youdong
Y
Shi
Changxin
C
Keating
Armand
A
Slutsky
Arthur
A
Zhang
Haibo
H
Wen
Xiao-Yan
XY
D056704:Adaptive Immunity / Q000235:genetics / Q000502:physiology*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015139:Blotting, Southern; D049109:Cell Proliferation; D022202:Chromosomes, Artificial, Bacterial; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D014443:Tyrosine