Human CD28 is essential for T-cell immunity to skin-tropic a- and g-papillomaviruses

In humans, α-papillomavirus HPV-2 and γ-papillomavirus HPV-4 typically cause common warts. In rare patients, HPV-2 may cause striking “tree man” manifestations. We describe here a patient with the HPV-2-driven “tree man” phenotype, and two of his distant relatives with unusually severe HPV4-driven warts. Genetic, transcriptional, and histological analyses of the “tree man” lesions showed that they formed a multifocal benign epithelial tumor driven by a specific HPV-2 strain. Surprisingly, all three patients are homozygous for a mutation of an essential splice site in the CD28 gene, which encodes an activating surface receptor on T cells. They have no detectable CD28 on their T cells, which, with the exception of a small contingent of revertant memory CD4+ T cells, do not respond to CD28 stimulation. Their T cells express normal levels of other costimulatory molecules and CTLA-4, and respond to CD2 stimulation. T- and B-cell development, and responses to antigens are otherwise normal in these individuals. Finally, CD28-deficient mice are vulnerable to cutaneous infections with the μ-papillomavirus MmuPV1. This experiment of Nature shows that the control of HPV-2 and HPV-4 in human keratinocytes is dependent on the T-cell CD28 co-activation pathway, which seems to be otherwise largely redundant in host defense. Naive CD4+of 4 controls and 1 CD28-/- patient were negatively sorted and stimulated with various combinations of mAb-coated beads