Effects of a constitutively active form of calcineurin on T cell activation and thymic selection
Effects of a constitutively active form of calcineurin on T cell activation and thymic selection
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DOI：
10.4049/jimmunol.165.7.3713
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发表时间：
2000-10-01
影响因子：
4.4
通讯作者：
Hedrick, SM
中科院分区：
文献类型：
--
作者：
Hayden-Martinez, K;Kane, LP;Hedrick, SM
钙调神经磷酸酶是一种钙/钙调素依赖的磷酸酶，其活性是诱导T细胞淋巴因子产生和增殖所必需的。尽管它在T细胞发育中的具体作用还不是很清楚，但对免疫抑制药物环孢素A和FK-506的研究表明，它参与了对未成熟胸腺细胞的阳性和阴性选择。为了更全面地描述钙调神经磷酸酶在体内T细胞发育中的作用，我们培育了在胸腺细胞和外周T细胞中表达这种酶的激活形式的转基因小鼠。我们发现，转基因导致胸腺早期发育受阻，导致稳定状态下的CD4和CD8双阳性数量减少，但对成熟T细胞的数量没有影响。我们还发现，胸腺细胞和表达该转基因的成熟T细胞通过其TCR对信号更敏感。在胸腺细胞中，这种敏感性差异表现为正向选择的增加，尽管负选择似乎仍未受到影响。因此，这些研究证实并扩展了过去关于钙调神经磷酸酶在胸腺发育和选择中的作用的报道。
Calcineurin is a calcium/calmodulin-dependent phosphatase whose activity is required for the induction of T cell lymphokine production and proliferation. Although its specific role in T cell development is less well defined, studies with the immunosuppressive drugs cyclosporin A and FK-506 suggest that it is involved in both positive and negative selection of immature thymocytes. To more completely characterize a role for calcineurin in T cell development in vivo, we have generated transgenic mice that express an activated form of this enzyme in thymocytes and peripheral T cells. We find that the transgene causes a block in early thymic development, resulting in a reduction in the steady-state number of CD4 and CD8 double positives, but not on the number of mature T cells. We also find that thymocytes and mature T cells expressing this transgene are more sensitive to signals through their TCR. In thymocytes this sensitivity difference is manifested as an increase in positive selection, although negative selection seems to remain unaffected. Therefore, these studies confirm and extend past reports that suggested a role for calcineurin in thymic development and selection.