Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy

Cell. 2021 Jul 8;184(14):3812-3828.e30. doi: 10.1016/j.cell.2021.06.004. Epub 2021 Jul 1.


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.

Keywords: CD28; HPV; T cell; cutaneous horn; immunodeficiency; oncogene; papillomavirus; somatic reversion; tree man syndrome; wart.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • CD28 Antigens / deficiency*
  • CD28 Antigens / genetics
  • CD28 Antigens / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • Child
  • Endopeptidases / metabolism
  • Female
  • Genes, Recessive
  • HEK293 Cells
  • Homozygote
  • Humans
  • Immunity, Humoral
  • Immunologic Memory
  • Inheritance Patterns / genetics*
  • Jurkat Cells
  • Keratinocytes / pathology
  • Male
  • Mice, Inbred C57BL
  • Oncogenes
  • Papilloma / pathology
  • Papilloma / virology
  • Papillomaviridae / physiology*
  • Pedigree
  • Protein Sorting Signals
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Skin / virology*
  • T-Lymphocytes / immunology*


  • CD28 Antigens
  • Protein Sorting Signals
  • RNA, Messenger
  • Endopeptidases
  • USP37 protein, human