We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro , they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity. [Display omitted] • Inherited human CD28 deficiency underlies severe HPV-2 and HPV-4 skin lesions • Human CD28 is otherwise largely redundant in protective immunity to infection • Inherited CD28 deficiency only slightly impairs T cell development and function • HPV-2 giant horns overexpress HPV oncogenes in the basal layer of the epidermis By studying a family of individuals with cutaneous protrusions and severe warts driven by human papilloma virus (HPV) infection, Béziat et al. discover that human CD28 is largely dispensable for protective immunity against most infections. Inherited CD28 deficiency only slightly impairs T cell development and function, but control of HPV in keratinocytes is dependent on the T cell CD28 co-activation pathway. [ABSTRACT FROM AUTHOR]