T cells homozygous for the −844C FASL polymorphism express more FASL when activated.

Death-prone T cells might increase the risk of developing cervical cancer, according to a study on page 967. Sun and colleagues show that women with cervical cancer are more likely to have T cells that are genetically programmed to express high levels of the death-inducing molecule FAS ligand (FASL).Most cervical cancers are associated with human papillomavirus (HPV) infection. But not all HPV-infected women develop cervical cancer, suggesting that other factors contribute to cancer progression. A recent study linked cervical cancer with a genetic polymorphism in the gene encoding the death receptor FAS, which triggers apoptosis when bound by its ligand FASL. However, these findings are controversial as other studies failed to confirm this association.

Sun and colleagues now find that a naturally occurring polymorphism in the FASL promoter was three times more prevalent in Chinese women with cervical cancer than in cancer-free controls. T cells with this single nucleotide polymorphism (−844C) expressed more FASL and were more prone to cell death after stimulation with cervical cancer cells than T cells without the polymorphism (−844T). Although the mechanism remains obscure, the authors suggest that an increased propensity for cell death might limit the ability of tumor-specific T cells to eradicate tumor cells.

The −844C polymorphism was recently found to improve the binding of a transcription factor that helps drive FASL gene expression, and to increase FASL protein levels on fibroblasts. In that study, the polymorphism was linked to the autoimmune disease systemic lupus erythematosus (SLE). The link to SLE was postulated to result from increased FAS-mediated cell death, which might facilitate the release of nuclear antigens that are then targeted by the immune response.