Miller A, Lider O, Weiner H L
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
J Exp Med. 1991 Oct 1;174(4):791-8. doi: 10.1084/jem.174.4.791.
Suppression of experimental autoimmune encephalomyelitis (EAE) in Lewis rats by the oral administration of myelin basic protein (MBP) is mediated by CD8+ T cells that can be isolated from the spleens of MBP-fed animals. These cells adoptively transfer protection to naive animals subsequently immunized with MBP and complete Freund's adjuvant (CFA) and suppress in vitro MBP proliferative responses. Using a transwell system in which the modulator spleen cells from MBP-fed animals are separated by a semipermeable membrane from responder cells, MBP, or OVA-specific T cell lines, we have found that cell contact is not required for in vitro suppression to occur. In vitro suppression is dependent, however, upon antigen-specific triggering of modulator T cells. Once antigen-specific triggering occurs, suppression across the transwell is mediated by an antigen-nonspecific soluble factor that equally suppresses an MBP line or an ovalbumin (OVA) line. This phenomenon of antigen-driven bystander suppression was also demonstrated in vivo. Specifically, Lewis rats fed OVA which were then immunized with MBP/CFA plus OVA given separately subcutaneously were protected from EAE. Animals fed OVA and then immunized with MBP/CFA without OVA given subcutaneously were not protected. The protective effect of feeding OVA could be adoptively transferred by CD8+ T cells from OVA-fed animals into MBP/CFA plus OVA-injected animals. Feeding bovine serum albumin (BSA) or keyhole limpet hemocyanin did not suppress EAE in animals immunized with MBP/CFA plus OVA. EAE was suppressed, however, if BSA was fed and animals then immunized with MBP/CFA plus BSA given subcutaneously. Antigen-driven bystander suppression appears to be an important mechanism by which antigen-driven peripheral tolerance after oral administration of antigen is mediated, and presumably occurs in the microenvironment accounting for the antigen specificity of suppression generated by oral tolerization to antigens.
通过口服髓鞘碱性蛋白（MBP）抑制Lewis大鼠实验性自身免疫性脑脊髓炎（EAE）是由CD8 + T细胞介导的，这些细胞可从喂食MBP的动物脾脏中分离得到。这些细胞可将保护作用过继转移至随后用MBP和完全弗氏佐剂（CFA）免疫的未致敏动物，并在体外抑制MBP增殖反应。使用一种Transwell系统，其中来自喂食MBP动物的调节性脾细胞通过半透膜与反应细胞、MBP或OVA特异性T细胞系分离，我们发现体外抑制作用的发生不需要细胞接触。然而，体外抑制作用依赖于调节性T细胞的抗原特异性触发。一旦发生抗原特异性触发，跨Transwell的抑制作用由一种抗原非特异性可溶性因子介导，该因子可同等程度地抑制MBP细胞系或卵清蛋白（OVA）细胞系。这种抗原驱动的旁观者抑制现象在体内也得到了证实。具体而言，喂食OVA的Lewis大鼠随后分别皮下注射MBP/CFA加OVA进行免疫，可免受EAE的侵害。喂食OVA然后皮下注射不含OVA的MBP/CFA进行免疫的动物则未受到保护。喂食OVA的保护作用可通过CD8 + T细胞从喂食OVA的动物过继转移至注射MBP/CFA加OVA的动物体内。喂食牛血清白蛋白（BSA）或钥孔戚血蓝蛋白并不能抑制用MBP/CFA加OVA免疫的动物的EAE。然而，如果喂食BSA并随后皮下注射MBP/CFA加BSA对动物进行免疫，EAE会受到抑制。抗原驱动的旁观者抑制似乎是口服抗原后介导抗原驱动的外周耐受的重要机制，并且可能发生在解释口服耐受抗原产生的抑制作用的抗原特异性的微环境中。
