Fayen J, Huang J H, Ferrone S, Tykocinski M L
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106-4943, USA.
Int Immunol. 1998 Sep;10(9):1347-58. doi: 10.1093/intimm/10.9.1347.
mAb with specificity for the alpha3 domain of HLA class I antigens, such as mAb TP25.99 and W6/32, are capable of inhibiting the proliferation of stimulated T cells in vitro by binding to their surface HLA class I antigens. The inhibitory potential of another HLA class I alpha3 domain-specific mAb, A1.4, was evaluated. In contrast to mAb TP25.99 and W6/32, which routinely inhibited superantigen (SEB) stimulation of T cells by >90%, mAb A1.4 at equivalent concentrations demonstrated only 20-50% inhibition. Univalent Fab fragments of all three mAb lacked inhibitory activity. Interestingly, however, by combining univalent W6/32 (or TP25.99) Fab fragments with intact, bivalent mAb A1.4 (at a non-inhibitory, sub-threshold concentration of 1 microg/ml), significant inhibition of SEB-driven T cell proliferation was obtained. Inhibition by the anti-HLA class I mAb W6/32 and TP25.99 was evident even when SEB was used in conjunction with paraformaldehyde-fixed HLA class I-, class II+ Daudi cells, suggesting that the inhibitory activity of these mAb results from direct HLA class I epitope engagement on the T cell. These findings suggest that effective antibody-mediated induction of the HLA class I inhibitory pathway within T cells is dependent upon two separable molecular triggers at the T cell surface. The first can be delivered by univalent mAb derivatives that engage one or more critical HLA class I epitope(s). The second requires intact mAb, though seems to be less selective as to the HLA class I specificity. This model may explain why some, but not all, anti-HLA class I mAb are inhibitory when used singly. Achieving synergies between a wider array of anti-HLA class I mAb and their derivatives may provide a path for more effectively tapping into the HLA class I inhibitory pathway in a therapeutic context.
对HLA I类抗原α3结构域具有特异性的单克隆抗体，如单克隆抗体TP25.99和W6/32，能够通过与受刺激T细胞表面的HLA I类抗原结合来抑制其在体外的增殖。评估了另一种HLA I类α3结构域特异性单克隆抗体A1.4的抑制潜力。与通常能抑制T细胞超抗原（SEB）刺激达90%以上的单克隆抗体TP25.99和W6/32不同，相同浓度的单克隆抗体A1.4仅表现出20%-50%的抑制作用。所有三种单克隆抗体的单价Fab片段均缺乏抑制活性。然而，有趣的是，通过将单价W6/32（或TP25.99）Fab片段与完整的二价单克隆抗体A1.4（以1μg/ml的非抑制性亚阈值浓度）结合，可显著抑制SEB驱动的T细胞增殖。即使将SEB与经多聚甲醛固定的HLA I类、II类+ Daudi细胞联合使用，抗HLA I类单克隆抗体W6/32和TP25.99的抑制作用依然明显，这表明这些单克隆抗体的抑制活性源于T细胞上直接的HLA I类表位结合。这些发现表明，T细胞内有效的抗体介导的HLA I类抑制途径的诱导取决于T细胞表面两个可分离的分子触发因素。第一个可由与一个或多个关键HLA I类表位结合的单价单克隆抗体衍生物传递。第二个需要完整的单克隆抗体，尽管对HLA I类特异性的选择性似乎较低。该模型可以解释为什么一些但不是所有的抗HLA I类单克隆抗体单独使用时具有抑制作用。在更广泛的抗HLA I类单克隆抗体及其衍生物之间实现协同作用，可能为在治疗背景下更有效地利用HLA I类抑制途径提供一条途径。
