Eagar Todd N, Karandikar Nitin J, Bluestone Jeffrey A, Miller Stephen D
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA.
Eur J Immunol. 2002 Apr;32(4):972-81. doi: 10.1002/1521-4141(200204)32:4<972::AID-IMMU972>3.0.CO;2-M.
T cell receptor engagement and the B7-CD28 / CTLA-4 signaling pathways play critical roles in T cell activation and regulation. CD28 engagement results in T cell activation, differentiation and survival while CTLA-4 signals block IL-2 production, cell cycle progression and T cell differentiation. We explored the role of CTLA-4 in peripheral tolerance induced by intravenous administration of ethylene carbodiimide-fixed, antigen-coupled splenocytes in the PLP139 - 151-induced relapsing experimental autoimmune encephalomyelitis system. Tolerance induction with PLP139 - 151-coupled splenocytes correlates with low B7 expression on the fixed antigen-presenting cells, conditions that would favor CTLA-4-mediated inhibition. Administration of CTLA-4Ig or anti-CTLA-4 concomitant with the 'tolerogenic' stimulus, however, failed to reverse tolerance induction. In contrast, blocking CTLA-4 at the time of secondary 'immunogenic' encounter with antigen reversed the tolerant state. These findings indicate that CTLA-4 is required to maintain the unresponsive state of the tolerized T cells upon antigenic stimulation under inflammatory conditions and, therefore, have important implications for therapeutic regulation of autoimmune disease.
T细胞受体的结合以及B7-CD28/CTLA-4信号通路在T细胞的激活和调节中起着关键作用。CD28的结合导致T细胞的激活、分化和存活，而CTLA-4信号则阻断白细胞介素-2的产生、细胞周期进程和T细胞分化。我们在PLP139 - 151诱导的复发性实验性自身免疫性脑脊髓炎系统中，探讨了CTLA-4在静脉注射碳二亚胺固定的、抗原偶联的脾细胞诱导的外周耐受中的作用。用PLP139 - 151偶联的脾细胞诱导耐受与固定的抗原呈递细胞上低水平的B7表达相关，这种情况有利于CTLA-4介导的抑制作用。然而，在给予“致耐受性”刺激的同时给予CTLA-4Ig或抗CTLA-4并不能逆转耐受的诱导。相反，在第二次与抗原发生“免疫原性”接触时阻断CTLA-4可逆转耐受状态。这些发现表明，在炎症条件下，抗原刺激时CTLA-4是维持耐受T细胞无反应状态所必需的，因此，对自身免疫性疾病的治疗调节具有重要意义。
