Murine myeloproliferative disorder as a consequence of impaired collaboration between dendritic cells and CD4 T cells.

Dendritic cells (DCs) are a key cell type in the initiation of the adaptive immune response. Recently an additional role for DCs in suppressing myeloproliferation was discovered. Myeloproliferative disorder (MPD) was observed in both murine studies with constitutive depletion of DCs, and in patients with congenital deficiency in DCs caused by mutations in GATA2 or IRF8 The mechanistic link between DC deficiency and MPD was not predicted through the known biology and has remained an enigma. Prevailing models suggest numerical DC deficiency leads to MPD through compensatory myeloid differentiation. Here we formally tested whether MPD can also arise through a loss of DC function without numerical deficiency. Using mice where DCs are deficient in antigen presentation, we find spontaneous myeloproliferative disorder characterized by splenomegaly, neutrophilia and extramedullary hematopoiesis, despite normal numbers of DCs. Disease development was dependent on loss of the MHC class II antigen presenting complex on DCs and was eliminated in mice deficient in total lymphocytes. Mice lacking both MHCII and CD4 T cells did not develop disease. MPD was thus paradoxically contingent on both the presence of CD4 T cells and on a failure of DCs to activate CD4 T cells, trapping the cells in a naïve Flt3L-expressing state. These results identify a novel requirement for intercellular collaboration between dendritic cells and CD4 T cells to regulate myeloid differentiation. Our findings support a new conceptual framework of DC biology in preventing MPD in mice and humans.