Noorchashm H, Moore D J, Noto L E, Noorchashm N, Reed A J, Reed A L, Song H K, Mozaffari R, Jevnikar A M, Barker C F, Naji A
Department of Surgery, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
J Immunol. 2000 Oct 15;165(8):4685-96. doi: 10.4049/jimmunol.165.8.4685.
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.
非肥胖糖尿病（NOD）小鼠的糖尿病是由I-A(g7)限制性胰岛反应性T细胞的激活引起的。本研究描述了NOD CD4 T细胞激活的几个特征，这些特征独立于I-A(g7)，可能会促进外周T细胞耐受性的失调状态。以细胞分裂进程为指标，发现NOD CD4 T细胞激活对通过TCR复合物的抗原刺激具有抗性。NOD CD4 T细胞分裂的程度对Ag配体密度的变化高度敏感。此外，即使在最大程度的TCR复合物介导的刺激下，NOD CD4 T细胞分裂也会过早终止。受到最大刺激的NOD CD4 T细胞未能达到激活诱导死亡最佳敏感性所需的分裂周期阈值数量，激活诱导死亡是调节外周T细胞耐受性的关键机制。重要的是，这些异常的激活特征并非T细胞内在固有，而是由于NOD小鼠依赖B细胞共刺激功能所致。非自身免疫性品系的抗原呈递细胞（APC）提供的共刺激使NOD CD4 T细胞分裂和激活诱导死亡的程度恢复正常。因此，通过破坏CD4 T细胞分裂进程，APC共刺激功能向B细胞区室的极化可能会使致糖尿病细胞在NOD小鼠中持续存在并被激活。
