St. Michael's Hospital, 30 Bond St., Queen Wing, Rm 8-019, Toronto, ON, Canada M5B 1W8.
FASEB J. 2010 Mar;24(3):947-56. doi: 10.1096/fj.09-140806. Epub 2009 Nov 18.
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.
Hacs1 是一种含有 SH3 和 SAM 结构域的衔接蛋白，在活化的 B 细胞中受 IL-4 上调，并在树突状细胞中强烈表达。为了阐明 Hacs1 在免疫调节中的功能，我们通过删除 SH3 和 SAM 结构域生成了 Hacs1(-/-) 小鼠。Hacs1(-/-) 小鼠存活和繁殖能力正常，骨髓 B 细胞发育正常，脾 T 和 B 细胞群体正常。然而，成年 Hacs1(-/-) 小鼠的腹腔 B1a 细胞（IgM(+)CD5(+))增加。在 T 细胞非依赖性抗原 TNP-Ficoll 免疫时，Hacs1(-/-) 小鼠产生更多的抗 TNP IgM 和 IgG3。从 Hacs1(-/-) 小鼠纯化的脾 B 细胞在 B 细胞受体（BCR）刺激下显示出更高的细胞增殖。我们进一步证明，Hacs1(-/-)B 细胞的整体酪氨酸磷酸化增加，包括酪氨酸激酶 Lyn 和 Akt。在 Hacs1(-/-) 小鼠中，T 辅助细胞 1（Th1）和 T 辅助细胞 2（Th2）体液反应均增强。体外骨髓来源的 Hacs1(-/-) 树突状细胞在刺激卵清蛋白（OVA）时显示出更高的 IL-12 产生。这项研究表明，Hacs1 是一种免疫抑制性衔接蛋白，可能是免疫抑制治疗的有用靶点。-Wang, D., Stewart, A. K., Zhuang, L., Zhu, Y., Wang, Y., Shi, C., Keating, A., Slutsky, A., Zhang, H., Wen, X.-Y. 缺乏免疫抑制性衔接蛋白 Hacs1 的小鼠适应性免疫增强。
