Oliveira-dos-Santos A J, Ho A, Tada Y, Lafaille J J, Tonegawa S, Mak T W, Penninger J M
Amgen Institute, Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.
J Immunol. 1999 Apr 15;162(8):4490-5.
Multiple sclerosis (MS) is a severe central nervous system disease. Experimental autoimmune encephalomyelitis (EAE) mimics MS in mice. We report that spontaneous development of EAE in RAG-1-deficient mice transgenic for a myelin basic protein (MBP)-specific TCR (TgMBP+/RAG-1-/-) requires expression of the T cell costimulatory molecule CD28. Surprisingly, T cells from CD28-/-TgMBP+/RAG-1-/- mice proliferate and produce IL-2 in response to MBP1-17 peptide in vitro, excluding clonal anergy as the mechanism of CD28-regulated pathogenesis. Proliferation of autoaggressive T cells was dependent on the concentration of the MBP peptide, as was the development of MBP-induced EAE in CD28-deficient PL/J mice. These results provide the first genetic evidence that CD28 costimulation is crucial for MBP-specific T cell activation in vivo and the initiation of spontaneous EAE.
多发性硬化症（MS）是一种严重的中枢神经系统疾病。实验性自身免疫性脑脊髓炎（EAE）在小鼠中模拟MS。我们报告，在转染了髓鞘碱性蛋白（MBP）特异性T细胞受体（TgMBP+/RAG-1-/-）的RAG-1缺陷小鼠中，EAE的自发发展需要T细胞共刺激分子CD28的表达。令人惊讶的是，来自CD28-/-TgMBP+/RAG-1-/-小鼠的T细胞在体外对MBP1-17肽有增殖反应并产生IL-2，排除了克隆无能作为CD28调节发病机制的可能性。自身攻击性T细胞的增殖取决于MBP肽的浓度，CD28缺陷的PL/J小鼠中MBP诱导的EAE的发展也是如此。这些结果提供了首个遗传学证据，表明CD28共刺激对于体内MBP特异性T细胞活化以及自发EAE的启动至关重要。
