Sato T, Nunomura S, Sato C, Hozumi K, Kumagai Y, Nishimura T, Mak T W, Kishihara K, Habu S
Department of Immunology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Int Immunol. 1999 Jan;11(1):89-97. doi: 10.1093/intimm/11.1.89.
The differentiation process from CD4-CD8- double-negative (DN) thymocytes to CD4+CD8+ double-positive (DP) stage is accompanied by vigorous proliferation. The resulting DP cells contain a sizable proportion of large cycling cells, but most DP cells are small resting cells. To explore the molecular mechanisms which regulate cell proliferation of DP thymocytes prior to further development, we used TCR-transgenic (Tg) mice with non-selecting MHC (Tg-Neut), which contain almost exclusively DP thymocytes that are not subject to either positive or negative selection. In Tg-Neut, the thymus contained DP cells of relatively large size, which showed higher extracellular signal-regulated kinase activity and enhanced responsiveness to mitogen compared to small DP cells. This indicates that all the large DP cells in the thymus are not positively selected and that they possess proliferative potential. When Tg-Neut mice were backcrossed with CD45 knockout mice (CD454-/- Tg-Neut), the thymus showed an increase of large DP cells and cycling cells, but a decrease of apoptotic cells. Furthermore, Bcl-2 expression and Jun N-terminal kinase activity, which are associated with resistance to apoptosis, were enhanced. These observations suggest that thymocyte proliferation in the DP stage is suppressed by a CD45-related process with regulation of mitogen-activated protein kinase and Bcl-2 unless DP cells receive TCR-mediated signals.
从CD4-CD8-双阴性（DN）胸腺细胞向CD4+CD8+双阳性（DP）阶段的分化过程伴随着旺盛的增殖。产生的DP细胞包含相当比例的大型循环细胞，但大多数DP细胞是小型静止细胞。为了探究在进一步发育之前调节DP胸腺细胞增殖的分子机制，我们使用了具有非选择性MHC的TCR转基因（Tg）小鼠（Tg-Neut），其几乎只含有不受阳性或阴性选择影响的DP胸腺细胞。在Tg-Neut中，胸腺含有相对较大尺寸的DP细胞，与小型DP细胞相比，这些细胞显示出更高的细胞外信号调节激酶活性以及对有丝分裂原的反应增强。这表明胸腺中所有的大型DP细胞并非经过阳性选择，并且它们具有增殖潜力。当Tg-Neut小鼠与CD45基因敲除小鼠（CD454-/- Tg-Neut）回交时，胸腺中大型DP细胞和循环细胞增加，但凋亡细胞减少。此外，与抗凋亡相关的Bcl-2表达和Jun N末端激酶活性增强。这些观察结果表明，除非DP细胞接收到TCR介导的信号，否则DP阶段的胸腺细胞增殖会受到与CD45相关的过程抑制，该过程涉及丝裂原活化蛋白激酶和Bcl-2的调节。
