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

The flt3 ligand (FL) is a growth and differentiation factor for primitive h ematopoietic precursors, dendritic cells, and natural killer cells, Human T lymphocytes express FL constitutively, but the cytokine is retained intrac ellularly within the Golgi complex. FL is mobilized from the cytoplasmic st ores 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 interle ukin (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 (mF L) and secretion of soluble FL (sFL) by human peripheral blood T lymphocyte s. The gammac-mediated signaling up-regulated FL in a T-cell receptor-indep endent manner. IL-2 and IL-7 stimulated both FL messenger RNA (mRNA) expres sion and translocation of FL protein to the cell surface. Cyclosporin A (Cs A) inhibited gammac-mediated trafficking of FL at the level of transition f rom 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 all ografts were reduced approximately 2-fold (P < .01) compared to patients re ceiving autologous grafts. The conclusion is that FL expression is controll ed by <gamma>c receptor signaling and that CsA interferes with FL release b y T cells. The link between gammac-dependent T-cell activation and FL expre ssion might be important for T-cell effector functions in graft acceptance and antitumor immunity after SCT. (C) 2001 by The American Society of Hemat ology.