Byth K F, Conroy L A, Howlett S, Smith A J, May J, Alexander D R, Holmes N
Department of Pathology, Cambridge University, United Kingdom.
J Exp Med. 1996 Apr 1;183(4):1707-18. doi: 10.1084/jem.183.4.1707.
The CD45 transmembrane glycoprotein has been shown to be a protein phosphotyrosine phosphatase and to be important in signal transduction in T and B lymphocytes. We have employed gene targeting to create a strain of transgenic mice that completely lacks expression of all isoforms of CD45. The spleens from CD45-null mice contain approximately twice the number of B cells and one fifth the number of T cells found in normal controls. The increase in B cell numbers is due to the specific expansion of two B cell subpopulations that express high levels of immunoglobulin (IgM) staining. T cell development is significantly inhibited in CD45-null animals at two distinct stages. The efficiency of the development of CD4-CD8- thymocytes into CD4+ CD8+ thymocytes is reduced by twofold, subsequently the frequency of successful maturation of the double positive population into mature, single positive thymocytes is reduced by a further four- to fivefold. In addition, we demonstrate that CD45-null thymocytes are severely impaired in their apoptotic response to cross-linking signals via T cell receptor (TCR) in fetal thymic organ culture. In contrast, apoptosis can be induced normally in CD45-null thymocytes by non-TCR-mediated signals. Since both positive and negative selection require signals through the TCR complex, these findings suggest that CD45 is an important regulator of signal transduction via the TCR complex at multiple stages of T cell development. CD45 is absolutely required for the transmission of mitogenic signals via IgM and IgD. By contrast, CD45-null B cells proliferate as well as wild-type cells to CD40-mediated signals. The proliferation of B cells in response to CD38 cross-linking is significantly reduced but not abolished by the CD45-null mutation. We conclude that CD45 is not required at any stage during the generation of mature peripheral B cells, however its loss reveals a previously unrecognized role for CD45 in the regulation of certain subpopulations of B cells.
CD45跨膜糖蛋白已被证明是一种蛋白酪氨酸磷酸酶，在T和B淋巴细胞的信号转导中起重要作用。我们利用基因靶向技术创建了一种转基因小鼠品系，该品系完全缺乏所有CD45同工型的表达。CD45基因敲除小鼠的脾脏中B细胞数量约为正常对照的两倍，T细胞数量为正常对照的五分之一。B细胞数量的增加是由于两个表达高水平免疫球蛋白（IgM）染色的B细胞亚群的特异性扩增。在两个不同阶段，CD45基因敲除动物的T细胞发育受到显著抑制。CD4-CD8-胸腺细胞发育为CD4+CD8+胸腺细胞的效率降低了两倍，随后双阳性群体成功成熟为成熟单阳性胸腺细胞的频率又降低了四到五倍。此外，我们证明，在胎儿胸腺器官培养中，CD45基因敲除的胸腺细胞对通过T细胞受体（TCR）交联信号的凋亡反应严重受损。相比之下，非TCR介导的信号可正常诱导CD45基因敲除胸腺细胞凋亡。由于阳性和阴性选择都需要通过TCR复合物的信号，这些发现表明CD45是T细胞发育多个阶段通过TCR复合物进行信号转导的重要调节因子。通过IgM和IgD传递促有丝分裂信号绝对需要CD45。相比之下，CD45基因敲除的B细胞对CD40介导的信号的增殖与野生型细胞一样。CD45基因敲除突变显著降低但并未消除B细胞对CD38交联的增殖反应。我们得出结论，在成熟外周B细胞的产生过程中，任何阶段都不需要CD45，然而其缺失揭示了CD45在调节某些B细胞亚群方面以前未被认识的作用。
