The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia.
The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia.
J Invest Dermatol. 2018 Jun;138(6):1348-1359. doi: 10.1016/j.jid.2017.12.021. Epub 2017 Dec 23.
Chemokines regulate tissue immunity by recruiting specific subsets of immune cells. Mice expressing the E7 protein of human papilloma virus 16 as a transgene from a keratin 14 promoter (K14.E7) show increased epidermal and dermal lymphocytic infiltrates, epidermal hyperplasia, and suppressed local immunity. Here, we show that CXCL9 and CXCL10 are overexpressed in non-hematopoietic cells in skin of K14.E7 mice when compared with non-transgenic animals, and recruit CXCR3 lymphocytes to the hyperplastic skin. Overexpression of CXCL9 and CXCL10 is not observed in E7 transgenic mice with mutated Rb gene whose protein product cannot interact with E7 (K14.E7xRb) and in consequence lack hyperplastic epithelium. CXCR3 T cells are preferentially recruited by CXCL9 and CXCL10 in supernatants of K14.E7 but not K14.E7xRb skin cultures in vitro. CXCR3 signalling promotes infiltration of a subset of effector T lymphocytes that enables donor lymphocyte deficient, E7-expressing skin graft rejection. Taken together, this suggests that recruitment of CXCR3 T cells can be an important factor in the rejection of precancerous skin epithelium providing they can overcome local immunosuppressive mechanisms driven by skin-resident lymphocytes.
趋化因子通过募集特定的免疫细胞亚群来调节组织免疫。表达人乳头瘤病毒 16 的 E7 蛋白作为角蛋白 14 启动子（K14.E7）的转基因的小鼠显示出增加的表皮和真皮淋巴细胞浸润、表皮增生和局部免疫抑制。在这里，我们发现与非转基因动物相比，K14.E7 小鼠皮肤中的非造血细胞中过度表达 CXCL9 和 CXCL10，并招募 CXCR3 淋巴细胞到增生的皮肤中。在 E7 转基因小鼠中，不能与 E7 相互作用的突变 Rb 基因（K14.E7xRb）的蛋白产物缺乏增生上皮，不会观察到 CXCL9 和 CXCL10 的过度表达。在体外，K14.E7 但不是 K14.E7xRb 皮肤培养物的上清液中，CXCR3 T 细胞优先被 CXCL9 和 CXCL10 募集。CXCR3 信号促进了效应 T 淋巴细胞的浸润，这些淋巴细胞使供体淋巴细胞缺陷、表达 E7 的皮肤移植物被排斥。综上所述，这表明 CXCR3 T 细胞的募集可能是癌前皮肤上皮排斥的一个重要因素，前提是它们能够克服由皮肤驻留淋巴细胞驱动的局部免疫抑制机制。
