Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists.
Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists.
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DOI：
10.1084/jem.20021024
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发表时间：
2003-04-21
期刊：
影响因子：
--
通讯作者：
Hünig T
中科院分区：
文献类型：
--
作者：
Lühder F;Huang Y;Dennehy KM;Guntermann C;Müller I;Winkler E;Kerkau T;Ikemizu S;Davis SJ;Hanke T;Hünig T
初始T细胞的充分激活需要T细胞抗原受体(TCR；信号1)的参与和CD28(信号2)的共刺激信号。我们以前发现了两种类型的大鼠CD28特异性单抗(MAbb)：一种是“常规的”依赖TCR信号的共刺激单抗；另一种是“超激动型”的单抗，它们能够在没有TCR结扎的情况下在体外和体内诱导原始静息T细胞的完全激活。利用嵌合的大鼠/小鼠CD28分子，我们发现超级激动剂仅与CD28免疫球蛋白样域的横向暴露的C‘’D环结合，而常规的共刺激单抗识别接近天然CD80/CD86配体结合部位的表位。出乎意料的是，一组针对人类CD28的新抗体的C‘’D环反应可以仅根据它们的超激动剂特性来预测。此外，小鼠CD28分子被设计来表达大鼠或人的C‘D环序列，当被超激动型单抗交联时，激活了没有TCR连接的T细胞杂交瘤。最后，生化分析表明，超激动型CD28信号激活核因子κB途径，而不诱导TCRZAP70或ζ的磷酸化。我们的发现表明，抗CD28超级激动剂的拓扑受限相互作用绕过了T细胞激活中对信号1的要求。具有这种特性的抗体可能会被证明对T细胞刺激药物的开发有用。
Full activation of naive T cells requires both engagement of the T cell antigen receptor (TCR; signal 1) and costimulatory signaling by CD28 (signal 2). We previously identified two types of rat CD28-specific monoclonal antibodies (mAbs): “conventional,” TCR signaling–dependent costimulatory mAbs and “superagonistic” mAbs capable of inducing the full activation of primary resting T cells in the absence of TCR ligation both in vitro and in vivo. Using chimeric rat/mouse CD28 molecules, we show that the superagonists bind exclusively to the laterally exposed C′′D loop of the immunoglobulin-like domain of CD28 whereas conventional, costimulatory mAbs recognize an epitope close to the binding site for the natural CD80/CD86 ligands. Unexpectedly, the C′′D loop reactivity of a panel of new antibodies raised against human CD28 could be predicted solely on the basis of their superagonistic properties. Moreover, mouse CD28 molecules engineered to express the rat or human C′′D loop sequences activated T cell hybridomas without TCR ligation when cross-linked by superagonistic mAbs. Finally, biochemical analysis revealed that superagonistic CD28 signaling activates the nuclear factor κB pathway without inducing phosphorylation of either TCRζ or ZAP70. Our findings indicate that the topologically constrained interactions of anti-CD28 superagonists bypass the requirement for signal 1 in T cell activation. Antibodies with this property may prove useful for the development of T cell stimulatory drugs.
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