Credit: S. Bradbrook/NPG

This study reports a new fate for immunostimulatory conventional dendritic cells (DCs). It shows that they can differentiate into immunosuppressive macrophage-like cells and indicates that tumours might have exploited this pathway to subvert the immune response.

Bone marrow-derived pre-DCs are irreversibly committed to become terminal DCs in peripheral tissues. To investigate this differentiation pathway in vitro, bone marrow-derived pre-DCs (which have a CD11c+MHC class II− phenotype) were cultured on a stromal monolayer of skin fibroblasts. After 2–3 days, pre-DCs gave rise to CD11c+MHC class II+ proliferating DCs that could stimulate lymphocyte proliferation. However, after 10–12 days of culture, none of the progeny expressed CD11c or MHC class II molecules. The authors excluded the direct differentiation of pre-DCs to CD11c−MHC class II− cells and showed that the CD11c−MHC class II− cells that arise in pre-DC–stromal cell culture are derived from CD11c+MHC class II+ DCs. Further experiments showed that addition of the DC growth factor GM-CSF to stromal cell cultures completely blocked the generation of CD11c−MHC class II− cells from CD11c+MHC class II+ DCs.

The CD11c−MHC class II− cells that were derived in vitro had typical features of macrophages, including high phagocytic capacity and expression of F4/80. DC maturation stimuli had little effect on the lymphocyte-stimulatory capacity of these cells and instead upregulated the expression of inducible nitric oxide synthase. Indeed, the CD11c−MHC class II− DC-derived 'macrophages' inhibited the antigen-specific proliferation of T cells in vitro in a dose-dependent manner, predominantly through the production of nitric oxide.

Using transgenic mice to track DC development in vivo, the authors showed that the generation of CD11c−MHC class II− DC-derived 'macrophages' is not a significant differentiation pathway for DCs under steady-state conditions. However, these cells were present at a significant level in subcutaneous tumours, but not spleens, of tumour-bearing mice. Studies in congenic mice confirmed that tumours can induce the generation of CD11c−MHC class II− macrophage-like cells from CD11c+ pre-DCs and immature DCs; this pathway could be blocked by the overexpression of GM-CSF by tumour cells.

This study describes a new mechanism for controlling the number and function of DCs during inflammation and adds to the controversy regarding the heterogeneity of and relationships between macrophages and DCs (see further reading).