Son Heehwa G, Ha Dat Thinh, Xia Yun, Li Tiancheng, Blandin Jasmine, Oka Tomonori, Azin Marjan, Conrad Danielle N, Zhou Can, Zeng Yuhan, Hasegawa Tatsuya, Strickley John D, Messerschmidt Jonathan L, Guennoun Ranya, Erlich Tal H, Shoemaker Gregory L, Johnson Luke H, Palmer Kenneth E, Fisher David E, Horn Thomas D, Neel Victor A, Nazarian Rosalynn M, Joh Joongho J, Demehri Shadmehr
Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
Cancer Cell. 2025 Jan 13;43(1):36-48.e10. doi: 10.1016/j.ccell.2024.11.013. Epub 2024 Dec 12.
Immunosuppression commonly disrupts the homeostasis of mutated normal skin, leading to widespread skin dysplasia and field cancerization. However, the immune system's role in maintaining the normal state of mutated tissues remains uncertain. Herein, we demonstrate that T cell immunity to cutaneotropic papillomaviruses promotes the homeostasis of ultraviolet radiation-damaged skin. Mouse papillomavirus (MmuPV1) colonization blocks the expansion of mutant p53 clones in the epidermis in a CD8 T cell-dependent manner. MmuPV1 activity is increased in p53-deficient keratinocytes, leading to their specific targeting by CD8 T cells in the skin. Sun-exposed human skin containing mutant p53 clones shows increased epidermal beta-human papillomavirus (β-HPV) activity and CD8 T cell infiltrates compared with sun-protected skin. The expansion of mutant p53 clones in premalignant skin lesions associates with β-HPV loss. Thus, immunity to commensal HPVs contributes to the homeostasis of mutated normal skin, highlighting the role of virome-immune system interactions in preserving aging human tissues.
免疫抑制通常会破坏突变正常皮肤的稳态，导致广泛的皮肤发育异常和场癌化。然而，免疫系统在维持突变组织正常状态中的作用仍不确定。在此，我们证明对亲皮性乳头瘤病毒的T细胞免疫促进了紫外线损伤皮肤的稳态。小鼠乳头瘤病毒（MmuPV1）定植以CD8 T细胞依赖性方式阻断表皮中突变p53克隆的扩增。MmuPV1活性在p53缺陷的角质形成细胞中增加，导致其在皮肤中被CD8 T细胞特异性靶向。与防晒皮肤相比，含有突变p53克隆的暴露于阳光的人类皮肤显示表皮β-人乳头瘤病毒（β-HPV）活性增加和CD8 T细胞浸润。癌前皮肤病变中突变p53克隆的扩增与β-HPV缺失相关。因此，对共生HPV的免疫有助于突变正常皮肤的稳态，突出了病毒组-免疫系统相互作用在保护衰老人体组织中的作用。
