Roles of membrane-bound lectins in the regulation of immune cells.

膜结合凝集素在免疫细胞调节中的作用。

• 批准号: 15390158
• 负责人: TSUBATA Takeshi
• 金额: $ 9.66万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390158/
• 关键词: B lymphocyte; BCR; signal transduction; CD22; CD72; ITIM; IgG; IgE; IgA; レクチン; BCR; 免疫グロブリン; アイソタイプ; 抗体産生

CD22 is a member of the siglec family and specifically recognizes a2,6 sialic acid, whereas CD72 contains a C-type lectin domain. These membrane-bound lectin molecules contain the immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region. Upon phosphorylation, these ITIMs recruit and activate the SH2 domain containing tyrosine phosphatase 1 (SHP1), thereby down-regulate BCR signaling. We demonstrated that CD22-mediated signal regulation depends on the immunoglobulin isotypes of BCR. Indeed, CD22 negatively regulates signaling through IgM-BCR, IgD-BCR and IgA-BCR, but not signaling through IgG-BCR or IgE-BCR. In the absence of CD22-mediated signaling inhibition, IgG-BCR and IgE-BCR transmit augmented signaling, which may be involved in rapid antibody production in memory responses. The cytoplasmic regions of membrane form of IgG and IgE are involved in abrogation of CD22-mediated signal inhibition. In contrast, CD72 regulates BCR signaling regardless of Ig isotypes. SHP-1 contains two SH2 domains, and at least two out of tree ITIMs in CD22 are suggested to be essential for recruitment of SHP-1. We demonstrated that one ITIM is sufficient for recruitment of SHP-1 to CD22 and CD22-mediated signal regulation. Moreover, tyrosine at the position 783 locating in an ITIM appears to regulate phosporylation of other tyrosines in the cytoplamic region of CD22. These findings are crucial for elucidation of the function of membrane-bound lectins, and development of new strategies for controlling B cell function.

CD 22是siglec家族的成员，特异性识别α 2，6唾液酸，而CD 72含有C型凝集素结构域。这些膜结合凝集素分子在细胞质区域含有基于免疫受体酪氨酸的抑制基序（ITIM）。在磷酸化后，这些ITIM募集并激活含有酪氨酸磷酸酶1（SHP 1）的SH 2结构域，从而下调BCR信号传导。我们证明了CD 22介导的信号调节依赖于BCR的免疫球蛋白同种型。事实上，CD 22通过IgM-BCR、IgD-BCR和IgA-BCR负调节信号传导，但不通过IgG-BCR或IgE-BCR负调节信号传导。在不存在CD 22介导的信号传导抑制的情况下，IgG-BCR和IgE-BCR传递增强的信号传导，其可能参与记忆应答中的快速抗体产生。膜形式的IgG和IgE的细胞质区域参与消除CD 22介导的信号抑制。相比之下，CD 72调节BCR信号传导，而不管IG同种型。SHP-1含有两个SH 2结构域，并且CD 22中的至少两个ITIM被认为对于SHP-1的募集是必需的。我们证明了一个ITIM足以募集SHP-1到CD 22和CD 22介导的信号调节。此外，位于ITIM中783位的酪氨酸似乎调节CD 22细胞质区域中其他酪氨酸的磷酸化。这些发现对于阐明膜结合凝集素的功能和开发控制B细胞功能的新策略至关重要。

项目成果

Hokazono, Y., Adachi, T., Wabl, M., Tada, N., Amagasa, T., Tsubata T.: "Inhibitory co-receptors activated by antigens but not by anti immunoglobulin heavy chain antibodies install requirement of co-stimulation through CD40 for survival and proliferation o

Hokazono，Y.，Adachi，T.，Wabl，M.，Tada，N.，Amagasa，T.，Tsubata T.：“由抗原激活的抑制性共受体，但不由抗免疫球蛋白重链抗体激活，需要共-

Involvement of cell cycle progression in survaival signaling through CD40 inB lymphocyte line Wehi-231.

通过 B 淋巴细胞系 Wehi-231 中的 CD40 参与细胞周期进程的生存信号传导。

• 发表时间: 2003
• 期刊: Cell. Death. Differ 11
• 作者: Hirai H;Adachi T;Tsubata T.
• 通讯作者: Tsubata T.

Inhibitory co-receptors activated by antigens but not by anti immunoglobulin heavy chain antibodies install requirement of co-stimulation through CD40 for survival and proliferation of B cells.

由抗原激活但不由抗免疫球蛋白重链抗体激活的抑制性共受体需要通过 CD40 进行共刺激才能使 B 细胞存活和增殖。

• 发表时间: 2003
• 期刊: J. Immunol. 171
• 作者: Hokazono;Y.;Adachi;T.;Wabl;M.;Tada;N.;Amagasa;T.;Tsubata' T.
• 通讯作者: Tsubata' T.

Suzuki, A, Kaisho, T., Ohishi, M., Tsukio-Yamaguchi, M., Tsubata T., Koni, P.A., Sasaki, T., Mak, T.W., Nakano, T。: "Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination."J.Exp.Med.. 197. 657-667 (2003)

铃木，A，Kaisho，T.，Ohishi，M.，Tsukio-Yamaguchi，M.，Tsubata T.，Koni，P.A.，Sasaki，T.，Mak，T.W.，Nakano，T.

Involvement of cell cycle progression in survival signaling through CD40 in B lymphocyte line WEHI-231

B 淋巴细胞系 WEHI-231 中通过 CD40 参与细胞周期进程的生存信号传导

• 发表时间: 2004
• 期刊: Cell Death Differ. 11
• 作者: Hirai;H.;Adachi;T.;Tsubata;T.
• 通讯作者: T.