Cell-surface trafficking and release of flt3 ligand from T lymphocytes is induced by common cytokine receptor γ-chain signaling and inhibited by cyclosporin A

The flt3 ligand (FL) is a growth and differentiation factor for primitive hematopoietic precursors, dendritic cells, and natural killer cells, Human T lymphocytes express FL constitutively, but the cytokine is retained intracellularly within the Golgi complex. FL is mobilized from the cytoplasmic stores and its serum levels are massively increased during the period of bone marrow aplasia after stem cell transplantation (SCT), Signals that trigger the release of FL by T cells remain unknown, This study shows that interleukin (IL)-2, IL-4, IL-7, and IL-15, acting through a common receptor gamma chain (gammac), but not cytokines interacting with other receptor families, are efficient inducers of cell surface expression of membrane-bound FL (mFL) and secretion of soluble FL (sFL) by human peripheral blood T lymphocytes. The gammac-mediated signaling up-regulated FL in a T-cell receptor-independent manner. IL-2 and IL-7 stimulated both FL messenger RNA (mRNA) expression and translocation of FL protein to the cell surface. Cyclosporin A (CsA) inhibited gammac-mediated trafficking of FL at the level of transition from the Golgi to the trans-Golgi network, Accordingly, serum levels of sFL and expression of mFL by T cells of CsA-treated recipients of stem cell allografts were reduced approximately 2-fold (P < .01) compared to patients receiving autologous grafts. The conclusion is that FL expression is controlled by <gamma>c receptor signaling and that CsA interferes with FL release by T cells. The link between gammac-dependent T-cell activation and FL expression might be important for T-cell effector functions in graft acceptance and antitumor immunity after SCT. (C) 2001 by The American Society of Hematology.