Distinct roles for transforming growth factor-beta(2) and tumour necrosis factor-alpha in immune deviation elicited by hapten-derivatized antigen-presenting cells

The role of antigen-presenting cells (APC) in the induction of antigen-spec ific unresponsiveness was examined, using two functionally distinct murine macrophage hybridomas, #59 and #63 cells. Derivatized with the hapten (dini trofluorobenzene; DNFB), #59 cells induced contact hypersensitivity (CH) in mice. Hapten-derivatized #63 cells failed to induce CH. Instead, they prev ented recipients from acquiring CH when exposed subsequently to a sensitizi ng dose of the hapten. Similarly, hapten-derivatized #59 cells, pretreated in vitro with transforming growth factor-p, (TGF-beta(2)) lost their capaci ty to evoke CH, and induced tolerance. Hapten-derivatized #63 cells and TGF -beta(2)-treated #59 cells eliminated CH in mice sensitized to hapten. Reve rse transcription-polymerase chain reaction analysis of mRNAs for various a ccessory molecules important in T-cell activation revealed that #63 and TGF -beta(2)-treated #59 cells differed only in their expression of tumour necr osis factor-alpha (TNF-alpha) mRNA. The latter expressed higher levels of T NF-alpha mRNA than did untreated #59 cells. As a consequence, #63 and TGF-b eta(2)-treated #59 cells, both of which induce tolerance, secrete TNF-alpha protein unlike untreated #59 cells, which do not induce tolerance to hapte n. Since neutralizing anti-TNF-alpha antibodies abrogated the tolerogenic p otential of #63 cells in vivo, we conclude that TGF-beta(2) equips hapten-b earing APC with the capacity to evoke systemic immune deviation in which CH is selectively silenced. We speculate that one effect of TGF-beta(2) is to cause APC to up-regulate TNF-alpha production. In turn, this cytokine bias es the functional property of responding hapten-specific T cells in a direc tion that not only interferes with acquisition, but suppresses induction of CH.