Apoptotic cell-directed resolution of lung inflammation requires myeloid αv integrin-mediated induction of regulatory T lymphocytes

Intratracheal instillation of apoptotic cells enhances resolution of experimental lung inflammation by incompletely understood mechanisms. We report that this intervention induces functional regulatory T lymphocytes (Tregs) in mouse lung experimentally inflamed by intratracheal administration of lipopolysaccharide (LPS). Selective depletion demonstrated that Tregs were necessary for maximal apoptotic cell-directed enhancement of resolution and adoptive transfer of additional Tregs was sufficient to promote resolution without administering apoptotic cells. After intratracheal instillation labelled apoptotic cells were observed in the majority of CD11c+CD103+ myeloid dendritic cells (DCs) migrating to mediastinal draining lymph nodes and bearing migratory and immunoregulatory markers including increased CCR7 and β8 integrin (ITGB8) expression. In mice deleted for αv integrin in the myeloid line so as to reduce phagocytosis of dying cells by CD103+DCs, exogenous apoptotic cells failed to induce TGF-β1 expression or Treg accumulation and also failed to enhance resolution of LPS-induced lung inflammation. We conclude that in murine lung, myeloid phagocytes encountering apoptotic cells can deploy αv integrin-mediated mechanisms to induce Tregs and enhance resolution of acute inflammation.