Commensal papillomavirus immunity preserves the homeostasis of highly mutated normal skin

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.