FIBROBLASTS PREVENT APOPTOSIS OF IL-2-DEPRIVED T-CELLS WITHOUT INDUCING PROLIFERATION - A SELECTIVE EFFECT ON BCL-X(L) EXPRESSION

The apoptosis of human cytokine-deprived activated T cells can be prev ented by a soluble mediator secreted by fibroblasts, epithelial and en dothelial cells, and this rescue occurs with fibroblasts from differen t species. Fractionation of WI38 fibroblast-conditioned medium indicat ed that the survival-promoting agent(s) were >30 000 MW. The continuou s presence of the survival factor was required for prevention of apopt osis, which did not involve the induction of proliferation. Neverthele ss, the co-cultured T cells remained in a primed state. The expression of the apoptosis-inducing proteins Bar and CD95 (Fas/Apo-1) was eithe r unchanged or slightly increased in fibroblast-rescued T cells, sugge sting that constraints on survival still existed after coculture. A fu ndamental observation in the present study was that although Bcl-2 was reduced, the levels of Bcl-x(L) was maintained in cytokine-deprived T cells by fibroblast co-culture. This suggests that fibroblasts and/or other stromal cells may promote activated T-cell survival by a select ive effect on Bcl-x(L) expression, which is consistent with histologic al examination of activated T cells within lymphoid tissue in vivo. Th e rescued T cells could be re-activated by CD3 antibody, but only in t he presence of CD28 co-stimulation, which induced both Bcl-2 and Bcl-x (L) expression and also proliferation. Thus, survival signals from str omal cells in tissue microenvironments may enable activated T-cell per sistence in a primed but quiescent state, and our data suggest that th e regulation of Bcl-x(L) expression may be central in this process. Th e further characterization of this process is essential to clarify how signals from stromal cells can influence the resolution and/or chroni city of immune responses in different tissues in vivo.