Cell-fate conversion of lymphoid-committed progenitors by instructive actions of cytokines

The primary role of cytokines in haemato-lymphopoiesis is thought to be the regulation of cell growth and survival(1-3). But the instructive action of cytokines in haematopoiesis has not been well addressed(4). Here we show t hat a clonogenic common lymphoid progenitor(5), a bone marrow-resident cell that gives rise exclusively to lymphocytes (T, B and natural killer cells) , can be redirected to the myeloid lineage by stimulation through exogenous ly expressed interleukin (IL)-2 and GM-CSF (granulocyte/ macrophage colony- stimulating factor) receptors. Analysis of mutants of the beta-chain of the IL-2 receptor revealed that the granulocyte- and monocyte-differentiation signals are triggered by different cytoplasmic domains, showing that the si gnalling pathway(s) responsible for these unique developmental outcomes are separable. Finally, we show that the endogenous myelomonocytic cytokine re ceptors for GM-CSF and macrophage colony-stimulating factor (M-CSF) are exp ressed at low to moderate levels on the more primitive haematopoietic stem cells, are absent on common lymphoid progenitors, and are upregulated after myeloid lineage induction by IL-2. We conclude that cytokine signalling ca n regulate cell-fate decisions and propose that a critical step in lymphoid commitment is downregulation of cytokine receptors that drive myeloid cell development.