Blocking of mixed lymphocyte reaction by spleen cells from total lymphoid-irradiated mice involves interruption of the IL-2 pathway

Abstract

Treatment with total lymphoid irradiation (TLI) before organ transplantation results in high incidences of donor-specific tolerance. However, the exact mechanism of how TLI induces or maintains tolerance is not known. In many experimental systems of tolerance, lack of IL-2 plays a central role in tolerance induction, as stimulation of immunocompetent cells with Ag in an insufficient IL-2 environment results in tolerance. To examine whether tolerance induction by TLI might involve the IL-2 pathway, we examined how TLI cells affect the ability of immunocompetent cells to produce IL-2 and express IL-2R in the MLR. Responder cells from MLR cultures in which cells from TLI-treated mice were added proliferated 50 to 70% less and produced 68 to 94% less IL-2 bioactivity than responder cells from control cultures. However, coculture of TLI cells into MLR did not alter IL-2R expression on responder cells, as measured by two-color FACS analysis. We found no evidence that TLI cells deleted MLR responder cells. Interestingly, exogenous IL-2 did not restore proliferation of MLR responder cells. These results suggest that TLI may induce tolerance by interrupting the IL-2 pathway in immunocompetent cells. Moreover, that exogenous IL-2 failed to restore immunocompetence suggests that tolerance in the TLI model may be easy to induce and very stable, and provides a rationale for the higher incidences of donor-specific tolerance after TLI treatment.