Perrin P J, Scott D, Quigley L, Albert P S, Feder O, Gray G S, Abe R, June C H, Racke M K
Immune Cell Biology Program, Naval Medical Research Institute, Bethesda, MD 20889.
J Immunol. 1995 Feb 1;154(3):1481-90.
T cell activation requires both Ag/MHC recognition and costimulatory signals. The present studies were designed to test whether the loss of tolerance to myelin basic protein (MBP) requires costimulation by members of the B7 receptor family. CTLA-4Ig, a fusion protein ligand for B7-1 and B7-2, was used to assess the role of B7-mediated costimulation in chronic relapsing experimental allergic encephalomyelitis (EAE) induced by the transfer of MBP specific T cell lines. In adoptively transferred EAE, administering CTLA-4Ig to donor mice or during in vitro activation of MBP specific-T cells resulted in diminution of clinical disease. The presence of CTLA-4Ig during both the immunization and in vitro activation stages was most effective in preventing clinical signs of disease. This diminution in clinical disease was paralleled by a decreased proliferative response and reduced production of IL-2 and IL-4, but not IFN-gamma, after antigenic stimulation of encephalitogenic T cells in vitro. In contrast, CTLA-4Ig treatment of recipient animals after the transfer of MBP-activated T cells affected neither disease course nor severity. These results indicate that additional costimulatory pathways may be involved in established EAE, or that some cells are independent of costimulation or, alternatively, that CTLA-4Ig does not enter brain parenchyma in therapeutic concentrations. Thus, we conclude that costimulation provided by B7 molecules plays a major role in the development of encephalitogenic T cells and in the establishment of chronic relapsing EAE, a prototypic CD4+ T cell-mediated autoimmune disease.
T细胞活化需要抗原/主要组织相容性复合体（Ag/MHC）识别和共刺激信号。本研究旨在测试对髓鞘碱性蛋白（MBP）耐受性的丧失是否需要B7受体家族成员的共刺激。CTLA-4Ig是一种针对B7-1和B7-2的融合蛋白配体，用于评估B7介导的共刺激在由MBP特异性T细胞系转移诱导的慢性复发性实验性自身免疫性脑脊髓炎（EAE）中的作用。在过继转移的EAE中，给供体小鼠施用CTLA-4Ig或在MBP特异性T细胞的体外活化过程中施用CTLA-4Ig，可导致临床疾病减轻。在免疫和体外活化阶段同时存在CTLA-4Ig在预防疾病的临床症状方面最为有效。临床疾病的这种减轻与体外抗原刺激致脑炎性T细胞后增殖反应降低以及白细胞介素-2（IL-2）和白细胞介素-4（IL-4）产生减少但干扰素-γ（IFN-γ）未减少相平行。相反，在转移MBP活化的T细胞后对受体动物进行CTLA-4Ig治疗，既不影响病程也不影响疾病严重程度。这些结果表明，其他共刺激途径可能参与已建立的EAE，或者某些细胞不依赖共刺激，或者CTLA-4Ig不会以治疗浓度进入脑实质。因此，我们得出结论，B7分子提供的共刺激在致脑炎性T细胞的发育以及慢性复发性EAE（一种典型的CD4 + T细胞介导的自身免疫性疾病）的建立中起主要作用。
