Evidence that stimulator cell-derived IL-6 and IL-1 are released in the mixed lymphocyte culture but are not requisite for responder T cell proliferation.

We investigated whether IL-6 and (or) IL-1 are crucial costimulatory signals in the human MLC with purified responder T cells. With allogeneic PBMC as stimulators, IL-6 and IL-1 were rapidly produced, and reached plateau values of 100-300 U/ml and 200-500 pg/ml after 24 hr, respectively. Irradiated or mitomycin-c treated PBMC could easily be induced (with LPS) to produce IL-6 and IL-1 while no activity was measured after 48 hr in the supernatant of PHA-stimulated T cells, suggesting that in the MLC the monokines were entirely produced by stimulator PBMC. In cultures of responder T cells and stimulator B cells, no IL-6 and IL-1 activity was measured in the supernatant, and only a marginal proliferative response was found. Exogenous IL-6 and IL-1 increased in a dose-dependent way the B-cell-induced alloresponse and induced significant cytotoxicity in the responder cells. Antisera to IL-6 and IL-1 totally inhibited the induced response. The proliferation was accompanied by increased IL-2 production and IL-2R expression. Preincubation of B cells with IL-6 and IL-1 did not improve the proliferation, suggesting direct effects of IL-6 and IL-1 on the T cells. The proliferative responses induced by B cells and exogenous IL-6 and IL-1 represented a fraction of those induced by PBMC. Moreover, in PBMC-stimulated cultures exogenous IL-6 and IL-1 or antisera to these lymphokines did not significantly alter proliferative responses, cytotoxicity, IL-2 levels in the supernatant, or IL-2R expression on responder T cells. We conclude that a role for IL-6 and IL-1 in allogeneic T cell stimulation can be demonstrated in conditions of suboptimal stimulation with B cells. With PBMC, neutralizing antisera to these cytokines do not seem to inhibit the proliferative response, suggesting that these cells are superior in alloantigen presentation either by producing various costimulatory signals or by the fact that due to cell-cell contact stimulator cell-derived monokines cannot be blocked. This finding makes it unlikely that antimonokine therapy will be useful in transplantation.