Srinivasan M, Wardrop R M, Gienapp I E, Stuckman S S, Whitacre C C, Kaumaya P T
Department of Microbiology, College of Biological Sciences, Ohio State University, Columbus, OH 43210, USA.
J Immunol. 2001 Jul 1;167(1):578-85. doi: 10.4049/jimmunol.167.1.578.
Complete activation of T cells requires two signals: an Ag-specific signal delivered via the TCR by the peptide-MHC complex and a second costimulatory signal largely provided by B7:CD28/CTLA-4 interactions. Previous studies have shown that B7 blockade can either ameliorate experimental autoimmune encephalomyelitis by interfering with CD28 signaling or exacerbate the disease by concomitant blockade of CTLA-4 interaction. Therefore, we developed a functional CD28 mimic to selectively block B7:CD28 interactions. The design, synthesis, and structural and functional properties of the CD28 free peptide, the end group-blocked CD28 peptide, and its retro-inverso isomer are shown. The synthetic T cell-costimulatory receptor peptides fold into a polyproline type II helical structure commonly seen in regions of globular proteins involved in transient protein-protein interactions. The binding determinants of CD28 can be transferred onto a short peptide mimic of its ligand-binding region. The CD28 peptide mimics effectively block the expansion of encephalitogenic T cells in vitro suggesting the potential usefulness of the peptides for the treatment of autoimmune disease conditions requiring down-regulation of T cell responses.
T细胞的完全激活需要两个信号：一个是由肽-MHC复合物通过TCR传递的抗原特异性信号，另一个是主要由B7:CD28/CTLA-4相互作用提供的共刺激信号。先前的研究表明，阻断B7可通过干扰CD28信号改善实验性自身免疫性脑脊髓炎，或通过同时阻断CTLA-4相互作用而加重疾病。因此，我们开发了一种功能性CD28模拟物以选择性阻断B7:CD28相互作用。展示了CD28游离肽、端基封闭的CD28肽及其反向异构体的设计、合成以及结构和功能特性。合成的T细胞共刺激受体肽折叠成多聚脯氨酸II型螺旋结构，这种结构常见于参与瞬时蛋白质-蛋白质相互作用的球状蛋白区域。CD28的结合决定簇可以转移到其配体结合区域的短肽模拟物上。CD28肽模拟物在体外有效阻断致脑炎性T细胞的扩增，表明这些肽对于治疗需要下调T细胞反应的自身免疫性疾病具有潜在用途。
