IL-12 Reverses Established Tolerance Mediated by Tcrαlβ⁺ but not by Tcrγδ⁺ Suppressor T Cells

Abstract

Topical cutaneous painting with chemically reactive haptens induces the ability to subsequently elicit contact sensitivity (CS) responses in the skin. These CS responses are in vivo examples of acquired, antigen (Ag)-specific T cell immunity, and are a form of delayed-type hypersensitivity (DTH). In contrast, high dose i.v. administration of the hapten can induce Ag-specific tolerance. In some instances this specific immune hyporeactivity is due to suppressor T cells. We investigated the effect of IL-12 on reversal of tolerance due to suppressor T cells that were induced by i.v. administration of hapten in either normal TCRα^+/+, or in immunodeficient TCRα^−/- mice. In the TCRα^+/+ mice, tolerance is mediated by TCRαβ⁺ suppressor T cells, while in the TCRα^−/- mice the tolerance is due to suppressive TCRγδ⁺ cells. Treatment with IL-12 reversed suppressor mediated by the TCRαβ⁺ cells, but did not affect tolerance due to TCRγδ⁺ suppressor cells. Another difference was that the αβTCR⁺ suppressor cells produced a soluble suppressor factor that could replace the surppressor cells, while γδTCR⁺ suppressor cells did not. We hypothesized that IL-12 may strengthen responses of target CS-effector T cells influenced by the hapten-MHC-specificity of αβ suppresssor cells, or suppressor factor. On the other hand, γδTCR⁺ suppressive cells likely have specificity for the hapten alone, and are not MHC-restricted, and therefore probably do not operate via peptide-MHC interactions, that could be strengthened by IL-12. The ability of IL-12 to strengthen the resistance of CS-effector T cells to αβ TCR suppressor cells, may be due to the ability of IL-12 to increase T cell costimulation mediated by signaling mechanisms acting via B7.1 and B7.2. In contrast, αβTCR⁺ suppressor cells, that are largely hapten-specific, probably do not interact with peptide/MHC complexes on APC, and thus are not affected by IL-12 strengthening of co-stimulation.