The role of interleukin-2 in proliferative responses in vitro of T cells from patients after bone marrow transplantation: evidence that minor defects can lead to in vitro unresponsiveness

We have studied lectin-induced interleukin-2 (IL-2) production and proliferation of peripheral blood mononuclear cells from patients who had undergone a successful allogeneic bone marrow transplantation. Shortly after transplantation, the T cells show a decreased proliferative response and a decreased IL-2 production. However, addition to the culture of exogenous IL-2 does not result in restoration of the proliferative response, which indicates that the low proliferative response is not due to decreased IL-2 production alone. Longitudinal studies show a substantial variation between patients in the time in which the capacity to produce IL-2 is restored; however, in all patients there is a period in which IL-2 production is still diminished, but the proliferative capacity, as measured upon addition of exogenous IL-2 to the culture, is almost within the normal range. Also during this period, the proliferative response of the T cells can be restored by the addition of irradiated "feeder cells" obtained from the bone-marrow donors, as these cells secrete IL-2 without consuming it. Because peripheral blood samples from patients after bone marrow transplantation show great imbalances in the distribution of T4/T8 subpopulations, we have studied the influence of an artificially produced "reverse T4/T8" ratio on the proliferative response to mitogen and (allos-)antigen stimulation of healthy donor T lymphocytes. Even at very low proportions of T4 cells, normal responses were obtained in the proliferation assays with polyclonal mitogens. Only the response to soluble antigens, such as tetanus toxoid, was impaired. However, a low proportion of T4 cells resulted in a low IL-2 production so that, when IL-2 is a limiting factor due to intrinsic defects of patient cells, an inverse T4/T8 ratio can cause a nonresponsiveness in in-vitro assays.