Figure 12.

Physiologic regulation of normal hematopoiesis by STAT3 vs STAT5 activating agents. Flt3L stimulates pan-differentiation of CD34^pos common myeloid and common lymphocyte precursors into CD11c^pos committed DC precursors via a STAT3-dependent process. This is markedly potentiated by IL-6 and G-CSF, but is dominantly suppressed by early exposure to GMCSF, due to inhibition of STAT3 activation and concomitant STAT5 activation. Such early GMCSF exposure instead favors differentiation of CD34^pos 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. Phenotypically conventional DCs generated by STAT3- vs STAT5-dependent pathways differ in many critical characteristics. It should be emphasized that although early exposure to GMCSF blocks STAT3-dependent DC differentation, later exposure of committed DC precursors to GMCSF may instead promote maturation and DC1-polarization, again by stimulating STAT5 and inhibiting STAT3.