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.

CD22 是 siglec 家族的成员，特异性识别 a2,6 唾液酸，而 CD72 包含 C 型凝集素结构域。这些膜结合凝集素分子在细胞质区域包含基于免疫受体酪氨酸的抑制基序 (ITIM)。磷酸化后，这些 ITIM 会招募并激活包含酪氨酸磷酸酶 1 (SHP1) 的 SH2 结构域，从而下调 BCR 信号传导。我们证明 CD22 介导的信号调节取决于 BCR 的免疫球蛋白同种型。事实上，CD22 通过 IgM-BCR、IgD-BCR 和 IgA-BCR 负向调节信号传导，但不通过 IgG-BCR 或 IgE-BCR 信号传导。在没有 CD22 介导的信号抑制的情况下，IgG-BCR 和 IgE-BCR 会传递增强的信号，这可能参与记忆反应中抗体的快速产生。 IgG 和 IgE 膜形式的细胞质区域参与 CD22 介导的信号抑制的消除。相比之下，CD72 调节 BCR 信号传导，无论 Ig 同种型如何。 SHP-1 包含两个 SH2 结构域，并且 CD22 中至少有两个树外 ITIM 被认为对于 SHP-1 的招募至关重要。我们证明，一个 ITIM 足以将 SHP-1 募集到 CD22 和 CD22 介导的信号调节中。此外，位于ITIM中783位的酪氨酸似乎调节CD22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以及开发控制 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.