Moalem G, Gdalyahu A, Shani Y, Otten U, Lazarovici P, Cohen I R, Schwartz M
Department of Neurobiology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
J Autoimmun. 2000 Nov;15(3):331-45. doi: 10.1006/jaut.2000.0441.
Neurotrophins (NTs) promote neuronal survival and maintenance during development and after injury. However, their role in the communication between the nervous system and the immune system is not yet clear. We observed recently that passively transferred activated T cells of various antigen specificities home to the injured central nervous system (CNS), yet only autoimmune T cells specific to a CNS antigen, myelin basic protein (MBP), protect neurons from secondary degeneration after crush injury of the rat optic nerve. Here we examined the involvement of NTs in T-cell-mediated neuroprotection, and the possible significance of the antigen specificity of the T cells in this activity. Analysis of cytokine and NT expression in various rat T cell lines showed that the T cells express mRNA for cytokines of Th1, Th2, and Th3 phenotypes. In addition, the T cells express mRNA and protein specific to nerve growth factor, brain-derived neurotrophic factor, NT-3, and NT-4/5. Antigen activation significantly increased NT secretion. Thus, reactivation of CNS autoimmune T cells by locally presented antigens to which they are specific can lead to enhanced secretion of NTs and possibly also of other factors in injured optic nerves. mRNA for TrkA, TrkB and p75 receptors was expressed in the injured nerve, suggesting that these specific receptors can mediate the effects of the T-cell-derived NTs. The neuroprotective effect of the passively transferred autoimmune anti-MBP T cells in injured optic nerves was significantly decreased after local applicaiton of a tyrosine kinase inhibitor known to be associated with NT-receptor activity. These results suggest that the neuroprotective effect of autoimmune T cells involves the secretion of factors such as NTs by the T cells reactivated by their specific antigen in the injured CNS. T cell intervention in the injured CNS might prove to be a useful means of promoting post-injury CNS maintenance and recovery, possibly via supply of NTs and other factors.
神经营养因子（NTs）在发育过程中和损伤后促进神经元的存活与维持。然而，它们在神经系统与免疫系统之间的通讯中的作用尚不清楚。我们最近观察到，被动转移的具有各种抗原特异性的活化T细胞归巢至受损的中枢神经系统（CNS），但只有对中枢神经系统抗原髓鞘碱性蛋白（MBP）特异的自身免疫性T细胞能在大鼠视神经挤压伤后保护神经元免受继发性退变。在此，我们研究了NTs在T细胞介导的神经保护中的作用，以及T细胞抗原特异性在该活性中的可能意义。对各种大鼠T细胞系中细胞因子和NTs表达的分析表明，T细胞表达Th1、Th2和Th3表型细胞因子的mRNA。此外，T细胞表达对神经生长因子、脑源性神经营养因子、NT-3和NT-4/5特异的mRNA和蛋白质。抗原激活显著增加NTs的分泌。因此，由局部呈递的其特异抗原重新激活中枢神经系统自身免疫性T细胞可导致受损视神经中NTs以及可能还有其他因子的分泌增加。TrkA、TrkB和p75受体mRNA在受损神经中表达，提示这些特异性受体可介导T细胞源性NTs的作用。在局部应用已知与NTs受体活性相关的酪氨酸激酶抑制剂后，被动转移的自身免疫性抗MBP T细胞在受损视神经中的神经保护作用显著降低。这些结果表明，自身免疫性T细胞的神经保护作用涉及由其在受损中枢神经系统中的特异性抗原重新激活的T细胞分泌诸如NTs等因子。T细胞对受损中枢神经系统的干预可能被证明是促进损伤后中枢神经系统维持和恢复的一种有用手段，可能是通过提供NTs和其他因子来实现。
