Contact sensitivity (CS) is a form of delayed‐type hypersensitivity to haptens applied epicutaneously and is thought to be mediated, like classical delayed‐type hypersensitivity responses, by CD4+ T helper‐1 cells. The aim of this study was to identify the effector T cells involved in CS. We studied CS to the strongly sensitizing hapten dinitrofluorobenzene (DNFB) in mice rendered deficient by homologous recombination in either major histocompatibility complex (MHC) class I, MHC class II, or both, and which exhibited deficiencies in, respectively, CD8+, CD4+, or both, T cells. MHC class I single‐deficient and MHC class I/class II double‐deficient mice, both of which have a drastic reduction in the number of CD8+ T cells, were unable to mount a CS response to DNFB. In contrast, both MHC class II‐deficient mice and normal mice treated with an anti‐CD4 monoclonal antibody (mAb) developed exaggerated and persistent responses relative to heterozygous control littermates. Furthermore, anti‐CD8 mAb depletion of class II‐deficient mice totally abolished their ability to mount an inflammatory response to DNFB. Removal of residual CD4+ T cells in class II‐deficient mice by anti‐CD4 mAb treatment did not diminish the intensity of CS. These data clearly demonstrate that class I‐restricted CD8+ T cells are sufficient for the induction of CS to DNFB, and further support the idea that MHC class II‐restricted CD4+ T cells down‐regulate this inflammatory response.

Contact hypersensitivity (CHS) is a T cell–mediated skin inflammation induced by epicutaneous exposure to haptens in sensitized individuals. We have previously reported that CHS to dinitrofluorobenzene in mice is mediated by major histocompatibility complex (MHC) class I–restricted CD8+ T cells. In this study, we show that CD8+ T cells mediate the skin inflammation through their cytotoxic activity. The contribution of specific cytotoxic T lymphocytes (CTLs) to the CHS reaction was examined both in vivo and in vitro, using mice deficient in perforin and/or Fas/Fas ligand (FasL) pathways involved in cytotoxicity. Mice double deficient in perforin and FasL were able to develop hapten-specific CD8+ T cells in the lymphoid organs but did not show CHS reaction. However, they did not generate hapten-specific CTLs, demonstrating that the CHS reaction is dependent on cytotoxic activity. In contrast, Fas-deficient lpr mice, FasL-deficient gld mice, and perforin-deficient mice developed a normal CHS reaction and were able to generate hapten-specific CTLs, suggesting that CHS requires either the Fas/FasL or the perforin pathway. This was confirmed by in vitro studies showing that the hapten-specific CTL activity was exclusively mediated by MHC class I–restricted CD8+ T cells which could use either the perforin or the Fas/FasL pathway for their lytic activity. Thus, cytotoxic CD8+ T cells, commonly implicated in the host defence against tumors and viral infections, could also mediate harmful delayed-type hypersensitivity reactions.