Role of interleukin-4 in down-regulation of contact sensitivity by γδ T cells from tolerized T-cell receptor α(-/-) mice

Abstract

Contact sensitivity (CS) is a classical example of an in vivo T-cell- mediated immune response that is under regulation. Such down-regulation can be mediated by αβ T cells in mice that are tolerized by prior exposure to high doses of antigen. In contrast, we demonstrated previously that such high-dose antigen tolerance in T-cell receptor (TCR) α(-/-) H-2(d) mice induced antigen-specific, apparently major histocompatibility complex- unrestricted, CD4- CD8- γδ T cells, that also could down-regulate CS responses antigen-specifically in vivo, and also inhibited in vitro production of IFN-γ. In the present experiments we employed H-2(b)-deficient TCRα(-/-) and TCRβ(-/-) mice, owing to different molecular constructs than were used previously, and confirmed that tolerized γδ T cells in these different H-2(b) αβ TCR (-/-) mice down-regulated CS. Thus, γδ T-cell suppressor function was not limited to mice bearing a special transgenic TCRα(-/-) DNA construct. Furthermore, employing monoclonal antibody and complement depletion in vitro and adoptive transfer in vivo, characterized the phenotype of these γδ down-regulatory T cells as: CD3+, CD28+, CD40- ligand+, Fas+, FcγR+ and NK1.1-. Also, in vitro antigen desensitization of these trinitrophenyl (TNP)-specific TCRγδ+ down-regulatory cells was achieved with soluble TNP-bovine serum albumin (BSA), but not with oxazolone- BSA, showing that these suppressive γδ T cells have antigen-specific receptors. Moreover, employing monoclonal antibody blocking of γδ suppressors in vitro, and of recipients in vivo, we showed that interleukin-4 (IL-4) was involved in this down-regulation of CS by γδ T cells, while IL- 10 and transforming growth factor-β2 were not. In summary, generation of antigen-specific, double-negative, γδ suppressor cells, by tolerance of high antigen doses in TCRα(-/-) mice, appears to be a general phenomenon, and IL-4 production is involved in their down-regulation of the T helper type 1 cells that mediate CS.