Schematic representation of postulated STAT-dependent DC differentiation pathways. Flt3L stimulates pan-differentiation of CD34pos common myeloid and common lymphocyte precursors into CD11c⁺ committed DC precursors via a STAT3-dependent process. This is markedly potentiated by IL-6, but is dominantly suppressed by step 1 exposure to GMCSF, due to inhibition of STAT3 activation and concomitant STAT5 activation (Figure 6A). Such step 1 GMCSF exposure instead favors differentiation of CD34⁺ common myeloid precursors into granulocyte/monocyte progenitors (rather than committed DC precursors). The granulocyte/monocyte progenitors achieve subsequent multilineage differentiation, including STAT5-dependent differentiation into conventional DCs and macrophages, and STAT5-independent differentiation into neutrophils (Figure 6B). Phenotypically conventional DCs generated by STAT3- versus STAT5-dependent pathways differ in many critical characteristics (Figures 1,Figure 2,Figure 3,Figure 4–5). It should be emphasized that although step 1 exposure to GMCSF blocks STAT3-dependent DC differentiation, step 2 exposure of committed DC precursors to GMCSF may instead promote maturation and DC1-polarization, again by stimulating STAT5 and inhibiting STAT3 (Figure 6A).