Fibroblasts prevent apoptosis of IL‐2‐deprived T cells without inducing proliferation: a selective effect on Bcl‐xL expression

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Abstract
The apoptosis of human cytokine-deprived activated T cells can be prevented by a soluble mediator secreted by fibroblasts, epithelial and endothelial cells, and this rescue occurs with fibroblasts from different species. Fractionation of WI38 fibroblast-conditioned medium indicated that the survival-promoting agent(s) were >30 000 MW. The continuous presence of the survival factor was required for prevention of apoptosis, which did not involve the induction of proliferation. Nevertheless, the co-cultured T cells remained in a primed state. The expression of the apoptosis-inducing proteins Bar and CD95 (Fas/Apo-1) was either unchanged or slightly increased in fibroblast-rescued T cells, suggesting that constraints on survival still existed after coculture. A fundamental 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 selective effect on Bcl-x(L) expression, which is consistent with histological examination of activated T cells within lymphoid tissue in vivo. The rescued T cells could be re-activated by CD3 antibody, but only in the presence of CD28 co-stimulation, which induced both Bcl-2 and Bcl-x(L) expression and also proliferation. Thus, survival signals from stromal cells in tissue microenvironments may enable activated T-cell persistence in a primed but quiescent state, and our data suggest that the regulation of Bcl-x(L) expression may be central in this process. The further characterization of this process is essential to clarify how signals from stromal cells can influence the resolution and/or chronicity of immune responses in different tissues in vivo.