Impaired CD4 T cell activation due to reliance upon B cell-mediated costimulation in nonobese diabetic (NOD) mice
Impaired CD4 T cell activation due to reliance upon B cell-mediated costimulation in nonobese diabetic (NOD) mice
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DOI：
10.4049/jimmunol.165.8.4685
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发表时间：
2000-10-15
影响因子：
4.4
通讯作者：
Naji, A
中科院分区：
文献类型：
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作者：
Noorchashm, H;Moore, DJ;Naji, A
非肥胖型糖尿病（NOD）小鼠的糖尿病是由I-A（g7）受限的胰岛反应性T细胞激活引起的。这项研究描述了NOD CD4 T细胞激活的几个特征，这些特征不依赖于I-A(g7)，可能会促进外周T细胞耐受的失调状态。NOD CD4 T细胞激活通过TCR复合物抵抗抗原刺激，使用细胞分裂进程作为衡量标准。NOD CD4 T细胞分裂程度对Ag配体密度的变化高度敏感。此外，即使在最大的TCR复合物介导的刺激下，NOD CD4 T细胞分裂也会过早终止。最大限度地刺激NOD CD4 T细胞未能达到激活诱导死亡的最佳易感性所需的分裂周期阈值，这是调节外周T细胞耐受性的关键机制。重要的是，这些异常的激活特征不是T细胞固有的，而是NOD小鼠依赖B细胞共刺激功能的结果。由非自身免疫性毒株APCs传递的共刺激使NOD CD4 T细胞分裂和激活诱导的死亡程度正常化。因此，通过破坏CD4 T细胞分裂的进程，APC对B细胞室的共刺激功能的极化可能允许NOD小鼠中致糖尿病细胞的持续和激活。
Diabetes in nonobese diabetic (NOD) mice results from the activation of I-A(g7)-restricted, islet-reactive T cells. This study delineates several characteristics of NOD CD4 T cell activation, which, independent of I-A(g7), are likely to promote a dysregulated state of peripheral T cell tolerance. NOD CD4 T cell activation was found to be resistant to antigenic stimulation via the TCR complex, using the progression of cell division as a measure. The extent of NOD CD4 T cell division was highly sensitive to changes in Ag ligand density. Moreover, even upon maximal TCR complex-mediated stimulation, NOD CD4 T cell division prematurely terminated. Maximally stimulated NOD CD4 T cells failed to achieve the threshold number of division cycles required for optimal susceptibility to activation-induced death, a critical mechanism for the regulation of peripheral T cell tolerance, Importantly, these aberrant activation characteristics were not T cell-intrinsic but resulted from reliance on B cell costimulatory function in NOD mice. Costimulation delivered by nonautoimmune strain APCs normalized NOD CD4 T cell division and the extent of activation-induced death. Thus, by disrupting the progression of CD4 T cell division, polarization of APC costimulatory function to the B cell compartment could allow the persistence and activation of diabetogenic cells in NOD mice.