Apoptotic cells induce CD103 expression and immunoregulatory function in myeloid dendritic cell precursors through integrin αv and TGF-β activation

In the mammalian gut CD103+ve myeloid DCs are known to suppress inflammation threatened by luminal bacteria, but stimuli driving DC precursor differentiation towards this beneficial phenotype are incompletely understood. We isolated CD11+ve DCs from mesenteric lymph nodes (MLNs) of healthy mice; CD103+ve DCs were 8-24 fold more likely than CD103-ve DCs to exhibit extensive of prior phagocytosis of apoptotic intestinal epithelial cells. However, CD103+ve and CD103-ve MLN DCs exhibited similar ex vivo capacity to ingest apoptotic cells, indicating that apoptotic cells might drive immature DC differentiation towards the CD103+ve phenotype. When cultured with apoptotic cells, myeloid DC precursors isolated from murine bone marrow and characterised as lineage-ve CD103-ve, displayed enhanced expression of CD103 and {beta}8 integrin and acquired increased capacity to induce Tregs after 7d in vitro. However, DC precursors isolated from v-tie2 mice lacking v integrins in the myeloid line exhibited reduced binding of apoptotic cells and complete deficiency in the capacity of apoptotic cells and/or latent TGF-{beta}1 to enhance CD103 expression in culture, whereas active TGF-{beta}1 increased DC precursor CD103 expression irrespective of v expression. Fluorescence microscopy revealed clustering of v integrin chains and latent TGF-{beta}1 at points of contact between DC precursors and apoptotic cells. We conclude that myeloid DC precursors can deploy v integrin to orchestrate binding of apoptotic cells, activation of latent TGF-{beta}1 and acquisition of the immunoregulatory CD103+ve {beta}8+ve DC phenotype. This implies that a hitherto unrecognised consequence of apoptotic cell interaction with myeloid phagocytes is programming that prevents inflammation.