Dennehy Kevin M, Elias Fernando, Zeder-Lutz Gabrielle, Ding Xin, Altschuh Danièle, Lühder Fred, Hünig Thomas
Institute for Virology and Immunobiology, University of Würzburg, Versbacherstrasse 7, 97078 Würzburg, Germany.
J Immunol. 2006 May 15;176(10):5725-9. doi: 10.4049/jimmunol.176.10.5725.
CD28 and CTLA-4 are the major costimulatory receptors on naive T cells. But it is not clear why CD28 is monovalent whereas CTLA-4 is bivalent for their shared ligands CD80/86. We generated bivalent CD28 constructs by fusing the extracellular domains of CTLA-4 or CD80 with the intracellular domains of CD28. Bivalent or monovalent CD28 constructs were ligated with recombinant ligands with or without TCR coligation. Monovalent CD28 ligation did not induce responses unless the TCR was coligated. By contrast, bivalent CD28 ligation induced responses in the absence of TCR engagement. To extend these findings to primary cells, we used novel superagonistic and conventional CD28 Abs. Superagonistic Ab D665, but not conventional Ab E18, predominantly ligates CD28 bivalently at low CD28/Ab ratios and induces Ag-independent T cell proliferation. Monovalency of CD28 for its natural ligands is thus essential to provide costimulation without inducing responses in the absence of TCR engagement.
CD28和CTLA-4是初始T细胞上主要的共刺激受体。但尚不清楚为何对于它们共同的配体CD80/86，CD28是单价的而CTLA-4是二价的。我们通过将CTLA-4或CD80的胞外结构域与CD28的胞内结构域融合，构建了二价CD28。二价或单价CD28构建体与有或没有TCR共刺激的重组配体连接。单价CD28连接除非TCR也被共刺激，否则不会诱导反应。相比之下，二价CD28连接在没有TCR参与的情况下就能诱导反应。为了将这些发现扩展到原代细胞，我们使用了新型超激动性和传统的CD28抗体。超激动性抗体D665而非传统抗体E18，在低CD28/抗体比例下主要以二价形式连接CD28，并诱导不依赖抗原的T细胞增殖。因此，CD28对其天然配体的单价性对于在没有TCR参与时提供共刺激而不诱导反应至关重要。
