Kumanogoh Atsushi, Shikina Takashi, Watanabe Chie, Takegahara Noriko, Suzuki Kazuhiro, Yamamoto Midori, Takamatsu Hyota, Prasad Durbaka V R, Mizui Masayuki, Toyofuku Toshihiko, Tamura Manabu, Watanabe Dai, Parnes Jane R, Kikutani Hitoshi
Department of Molecular Immunology, Research Institute for Microbial Diseases and CREST Program of JST, Osaka University, Suita, Japan.
Int Immunol. 2005 Oct;17(10):1277-82. doi: 10.1093/intimm/dxh307. Epub 2005 Aug 19.
Co-receptors on the B-cell surface regulate B-cell antigen receptor (BCR) signaling; however, it remains unclear how BCR signals are coordinated to maintain immune homeostasis. CD72, a negative regulator of B-cell responses, has immunoreceptor tyrosine-based inhibitory motifs within its cytoplasmic region, and the tyrosine phosphatase SHP-1 binds these sites. The natural ligand of CD72, CD100/Sema4D, belongs to the semaphorin family and induces the dissociation of SHP-1 from CD72, thereby switching off the negative signals of CD72. In the absence of CD100, BCR signals are significantly suppressed due to the constitutive association of SHP-1 with CD72, resulting in B-cell hyporesponsiveness. Here we show that CD100 regulates the sensitivity of the BCR by preventing the association of the CD72 with BCR, and this interaction is required for proper B-cell homeostasis. Consequently, as CD100-deficient mice age, they accumulate marginal zone B cells and develop high auto-antibody levels and autoimmunity. Collectively, our findings indicate that the strength of BCR signals is strictly tuned by the interaction of CD100 with CD72, and this interaction is essential for maintaining immunological homeostasis as well as generating a proper immune response.
B细胞表面的共受体调节B细胞抗原受体（BCR）信号传导；然而，BCR信号如何协调以维持免疫稳态仍不清楚。CD72是B细胞反应的负调节因子，在其胞质区域内具有基于免疫受体酪氨酸的抑制基序，酪氨酸磷酸酶SHP-1结合这些位点。CD72的天然配体CD100/Sema4D属于信号素家族，可诱导SHP-1与CD72解离，从而关闭CD72的负信号。在没有CD100的情况下，由于SHP-1与CD72的组成性结合，BCR信号被显著抑制，导致B细胞低反应性。在这里，我们表明CD100通过阻止CD72与BCR的结合来调节BCR的敏感性，并且这种相互作用是适当的B细胞稳态所必需的。因此，随着CD100缺陷小鼠年龄的增长，它们会积累边缘区B细胞，并产生高水平的自身抗体和自身免疫。总的来说，我们的研究结果表明，BCR信号的强度通过CD100与CD72的相互作用严格调节，并且这种相互作用对于维持免疫稳态以及产生适当的免疫反应至关重要。
