Cytotoxicity Is Mandatory for CD8+ T Cell–mediated Contact Hypersensitivity

Abstract

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.

Allergic contact dermatitis: the cellular effectors

“…Mice lacking perforin and/or Fas/Fas ligand pathways necessary for T cell-mediated cytotoxity were compared with wild-type animals. It was found that although mice lacking both pathways were able to generate hapten-specific CD8 π T lymphocytes, they were unable to mount CHS reactions (34). Similar conclusions regarding the importance of Fas-induced cell death in the pathogenesis of allergic contact dermatitis and other cutaneous inflammatory reactions derived from studies of human skin (35).…”

“…The question is to what extent cytotoxic mechanisms are required for CHS reactions effected by CD8 π cells, or other cellular effectors. The need for cytotoxic activity was investigated in a mouse model of CHS to DNFB in which the predominant or exclusive effectors were found to be CD8 π cells (34). Mice lacking perforin and/or Fas/Fas ligand pathways necessary for T cell-mediated cytotoxity were compared with wild-type animals.…”

IL-4 Enhances Keratinocyte Expression of CXCR3 Agonistic Chemokines

“…In C and D are CD4 ϩ and CD8 ϩ T cell lines, respectively, prepared from the skin of a third patient. direct cytotoxicity (7,13,22). ACD is generally considered as a model of Th1 cell-mediated disorder.…”

Lysophosphatidylcholine is a natural adjuvant that initiates cellular immune responses

“…Upon skin painting, the hapten is taken up by skin DC which migrate to proximal lymph nodes and activate specific T cells. Since the hapten can stay in the skin for a few days in its antigenic form, effector CD8 + T cells are recruited and activated in the dermis and induce CHS through a process involving cytotoxicity and IFNγ synthesis [38,39]. We used suboptimal concentrations of DNFB so that the CHS reaction observed at day 5 was only moderate in intensity and magnitude (Fig.…”