A Genetic Defect Impairs T Cells Surveillance of Skin Viruses

Immune cells are vigilant sentinels stationed at their tissue posts, such as the skin, lungs, or gut, or circulating in the bloodstream. Their presence and ability to quickly mobilize are key defenses against pathogens. For example, in healthy individuals, skin immune cells remove commensal human papillomaviruses (HPVs) from infected cells. However, in people with a rare genetic condition known as epidermodysplasia verruciformis (EV), these normally harmless HPVs are not cleared, which can lead to warts and non-melanoma skin cancer.

Some evidence suggests that errors in T cell immunity are linked to EV. This motivated researchers from The Rockefeller University and their colleagues to look for potential genetic variants in patients with EV.

In a recent study, published in Science Immunology, they found that several patients with EV carried a mutation in a gene related to immune cell migration, thus compromising skin defense and rendering these individuals more susceptible to commensal skin HPVs.¹ These findings reveal a genetic component to EV that influences T cell-mediated skin defense.

The researchers examined 62 unrelated patients with EV and discovered that 22 carried harmful variants in genes already known to cause the condition. However, the genetic basis in the remaining patients remained unclear. Further investigation revealed that several of them carried inherited variants of the integrin subunit alpha L (ITGAL) gene, which encodes the αL integrin chain. This protein pairs with the β2 chain to form the integrin lymphocyte function-associated antigen-1 (LFA-1), which is broadly expressed on leukocytes such as T cells.

Using human embryonic kidney cells transfected with wild type or patient-derived αL variants, the researchers found that the mutant αL proteins resulted in a loss of LFA-1 expression on the surface of T cells. This defect had functional consequences. In integrin-dependent chemotactic motility assays, cells carrying ITGAL mutations failed to migrate, whereas wild type cells displayed robust movement toward the chemokine C-X-C motif chemokine ligand 12. Consistent with these findings, leukocytes from affected patients also showed markedly reduced LFA-1 expression and impaired migratory capacity.

Because skin memory T cells normally recirculate continuously between the blood and the skin, they contribute to skin defense. In this case, although LFA-1-deficient memory T cells developed and differentiated normally, they were unable to home into the skin and instead accumulated in the bloodstream.

Notably, these findings identify ITGAL variants as contributors to the genetic basis of EV, as such variations permit unchecked viral proliferation in the skin, leading to lesions and cutaneous warts.