Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Department of Pathobiology, Institute of Immunology, University of Veterinary Medicine Vienna, Vienna, Austria.
J Immunol. 2021 Nov 15;207(10):2473-2488. doi: 10.4049/jimmunol.2100174. Epub 2021 Oct 8.
Because of its size, anatomical similarities, and now also accessibility to genetic manipulations, pigs are used as animal models for human diseases and immune system development. However, expression and function of CD28, the most important costimulatory receptor expressed by T cells, so far is poorly understood in this species. Using a newly generated mAb (mAb 3D11) with specificity for pig CD28, we detected CD28 on CD8 and CD4 αβ T cells. Among γδ T cells, CD28 expression was restricted to a small CD2 subpopulation of phenotypically naive cells. Functionally, CD28 ligation with mAb 3D11-costimulated porcine T cells, enhanced proliferation and cytokine secretion in vitro. We used a second, likewise newly generated but superagonistic, anti-CD28 mAb (CD28-SA; mAb 4D12) to test the function of CD28 on porcine T cells in a pilot study in vivo. Injection of the CD28-SA into pigs in vivo showed a very similar dose-response relationship as in humans (i.e., 100 µg/kg body weight [BW]) of CD28-SA induced a cytokine release syndrome that was avoided at a dose of 10 µg/kg BW and below. The data further suggest that low-dose (10 µg/kg BW) CD28-SA infusion was sufficient to increase the proportion of Foxp3 regulatory T cells among CD4 T cells in vivo. The pig is thus a suitable animal model for testing novel immunotherapeutics. Moreover, data from our pilot study in pigs further suggest that low-dose CD28-SA infusion might allow for selective expansion of CD4 regulatory T cells in humans.
由于其体型、解剖结构相似，并且现在也可以进行基因操作，因此猪被用作人类疾病和免疫系统发育的动物模型。然而，迄今为止，这种物种中 CD28 的表达和功能（T 细胞表达的最重要的共刺激受体）仍知之甚少。我们使用一种新生成的特异性针对猪 CD28 的 mAb（mAb 3D11），检测到 CD28 在 CD8 和 CD4αβT 细胞上的表达。在γδT 细胞中，CD28 的表达仅限于表型幼稚细胞的一个小 CD2 亚群。功能上，用 mAb 3D11 交联 CD28 可刺激猪 T 细胞体外增殖和细胞因子分泌。我们使用第二种同样新生成但具有超强激动作用的抗 CD28 mAb（CD28-SA；mAb 4D12），在体内进行了一项初步研究，以测试 CD28 在猪 T 细胞上的功能。体内注射 CD28-SA 显示出与人类非常相似的剂量反应关系（即，100μg/kg 体重[BW]），10μg/kg BW 及以下剂量的 CD28-SA 可避免引起细胞因子释放综合征。这些数据进一步表明，低剂量（10μg/kg BW）CD28-SA 输注足以增加体内 CD4 T 细胞中 Foxp3 调节性 T 细胞的比例。因此，猪是测试新型免疫疗法的合适动物模型。此外，我们在猪中的初步研究数据进一步表明，低剂量 CD28-SA 输注可能允许在人类中选择性扩增 CD4 调节性 T 细胞。
