Disparate cytotoxic activity of nickel-specific CD8(+) and CD4(+) T cell subsets against keratinocytes

Allergic contact dermatitis (ACD) is the result of an exaggerated immune re action to haptens mediated by skin-homing T cells, but the effector mechani sms responsible for the tissue damage are poorly understood. Here we studie d the capacity of distinct subsets of hapten-specific T cells to induce apo ptosis in autologous keratinocytes, Skin- and blood-derived nickel-specific CD8(+) T cytotoxic 1 (Tc1) and Tc2 clones as well as CD4(+) Th1 and Th2 ex pressed the cutaneous lymphocyte-associated Ag and exhibited strong MHC-res tricted cytotoxicity against nickel-coupled B lymphoblasts, as detected by the [H-3]TdR release assay. Both Tc1 and Tc2 clones, but not CD4(+) T cells , displayed a significant cytotoxic activity against resting nickel-modifie d keratinocytes, Following IFN-gamma treatment, keratinocytes expressed MHC class II and ICAM-1 and became susceptible to Th1-mediated, but not Th2-me diated, cytotoxicity. The molecules of the two major cytotoxic pathways, Fa s ligand (FasL) and perforin, were expressed by Tc1, Tc2, and Th1 cells, wh ereas Th2 cells expressed only Fast. Experiments performed in the presence of specific inhibitors of the perforin (concanamycin A) and Fast (brefeldin A) pathway indicated that perforin-mediated killing dominated in Tc1 and T c2, and Fast-mediated cytotoxicity prevailed in Th2 clones, with a more het erogeneous behavior in the case of Th1 cells. Finally, perforin mRNA was ex pressed in ACD lesional skin, as assessed by RT-PCR analysis. In aggregate, our results indicate that keratinocytes can be target of multiple hapten-s pecific CTL responses, that may have distinct roles in the epidermal injury during ACD.