The University of Queensland Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, Woolloongabba, Qld, Australia.
Exp Dermatol. 2010 Aug;19(8):723-9. doi: 10.1111/j.1600-0625.2010.01092.x.
Although IL-1 is a known inflammatory cytokine during pathogen infection, the role of IL-1 in skin graft rejection, particularly where foreign antigen is expressed exclusively in keratinocytes, is less understood. Here, we use a syngeneic skin graft system, where antigens are expressed in epithelial cells via either a keratin 14 or keratin 5 promoter, to explore the role of IL-1 in graft rejection and induction of epithelial antigen-specific effector CD8(+) T-cell function. Keratin 5 ovalbumin (K5mOVA) transgenic skin grafts destined for rejection demonstrated increased expression of IL-1beta and its receptors compared to K14 HPV16 E7 transgenic grafts that do not reject spontaneously. Rejection of OVA grafts lacking the IL-1 receptor (IL-1R1) was delayed and associated with decreased numbers of antigen-specific CD8 T cells. In contrast, K14E7 grafts survived on immunocompetent, syngeneic recipients with decreased graft levels of IL-1beta and IL-1R1 and 2. However, in the absence of the IL-1 receptor antagonist, IL-1Ra, skin grafts were spontaneously rejected and an E7-specific CD8 T-cell response was primed. Thus, expression of the HPV16E7 oncoprotein in epithelial cells prevents IL-1beta-associated skin graft rejection and induction of antigen-specific CD8 T-cell responses. Enhancing IL-1beta signalling, via blocking of the IL-1 receptor antagonist, may represent an alternative strategy for treatment of HPV16E7-associated cancers.
虽然白细胞介素-1（IL-1）是病原体感染过程中的一种已知炎性细胞因子，但它在皮肤移植物排斥反应中的作用，尤其是在仅角质形成细胞表达外来抗原的情况下，人们了解得较少。在这里，我们使用了一种同基因皮肤移植物系统，其中抗原通过角蛋白 14 或角蛋白 5 启动子在上皮细胞中表达，以探讨白细胞介素-1 在移植物排斥反应和诱导上皮抗原特异性效应 CD8+T 细胞功能中的作用。与不会自发排斥的 K14HPV16E7 转基因移植物相比，注定要被排斥的 K5mOVA 转基因皮肤移植物表现出更高水平的白细胞介素-1β及其受体的表达。缺乏白细胞介素-1 受体（IL-1R1）的 OVA 移植物的排斥反应被延迟，并伴有抗原特异性 CD8 T 细胞数量减少。相反，在具有免疫能力的同基因受体内，K14E7 移植物存活，其移植物中的白细胞介素-1β和白细胞介素-1R1 和 2 水平降低。然而，在缺乏白细胞介素-1 受体拮抗剂（IL-1Ra）的情况下，皮肤移植物会被自发排斥，并且会引发 E7 特异性 CD8 T 细胞反应。因此，上皮细胞中 HPV16E7 癌蛋白的表达可防止与白细胞介素-1β相关的皮肤移植物排斥反应和诱导抗原特异性 CD8 T 细胞反应。通过阻断白细胞介素-1 受体拮抗剂增强白细胞介素-1β信号，可能代表治疗 HPV16E7 相关癌症的另一种策略。
