MONOCYTES CONTROL GAMMA DELTA T-CELL RESPONSES BY A SECRETED PRODUCT/

Gamma-irradiated ex vivo bovine monocytes induce proliferation of gamm a/delta T cells in the autologous mixed lymphocyte reaction (AMLR), wh ereas when not irradiated they prevent this response. In contrast, non -irradiated autologous monocytes have no effect on bovine alpha/delta T-cell proliferation in the allogenic MLR suggesting that the regulati on is specific for gamma/delta T-cell responses. Here, we showed that the inhibition was not mediated by inducing cell death and that the ab ility of ex vivo monocytes to prevent proliferation of gamma/delta T c ells was not generalized in that gamma/delta T cells still responded t o mitogenic stimulation. Inhibition of the AMLR by non-irradiated mono cytes could not be overcome by addition of interleukin-2 to the cultur es or by costimulation with antibodies to WCl, a gamma/delta T-cell-sp ecific cell-surface differentiation antigen shown elsewhere by us to b e involved in activation of gamma/delta T cells. Furthermore, we showe d that monocytes inhibited gamma/delta T-cell responses via a soluble product since inhibition occurred even when monocytes and gamma/delta T cells were separated by membranes of transwells or when supernatants from monocyte cultures were added to AMLR cultures. Maximal secretion of the inhibitory product by the monocytes occurred during the first 6 hr of in vitro culture at 37 degrees, rapidly decreased thereafter, and did not occur when monocytes were incubated at 4 degrees. The inhi bition was not attributable to nitric oxide, reactive oxygen intermedi ates, prostaglandin E(2) or transforming growth factor-beta (TGF-beta) but the ability of monocyte supernatants to mediate inhibition was se nsitive to heating at 65 degrees. Lipopolysaccharide and granulocyte-m acrophage colony-stimulating factor activation of monocytes temporaril y abrogated their ability to inhibit proliferation. In contrast, heat- shocking had no effect on their ability to inhibit. We hypothesize tha t non-irradiated monocytes produce the inhibitory material in vivo in order to regulate gamma/delta T-cell responses to self-derived monocyt e membrane components, but that when monocytes are altered by infectio n, transformation, irradiation, or cytokine activation, production of the inhibitor is temporarily suspended allowing stimulation of gamma/d elta T cells to occur.