Apoptotic Cell-Directed Resolution of Lung Inflammation Requires Myeloid alpha v Integrin-Mediated Induction of Regulatory T Lymphocytes

摘要

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. 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, labeled apoptotic cells were observed in most CD11c(+)CD103(+) myeloid dendritic cells migrating to mediastinal draining lymph nodes and bearing migratory and immunoregulatory markers, including increased CCR7 and beta 8 integrin (ITGB8) expression. In mice deleted for alpha v integrin in the myeloid line to reduce phagocytosis of dying cells by CD103(+) dendritic cells, exogenous apoptotic cells failed to induce transforming growth factor-beta 1 expression or Treg accumulation and failed to enhance resolution of lipopolysaccharide-induced lung inflammation. We conclude that in murine lung, myeloid phagocytes encountering apoptotic cells can deploy alpha v integrin-mediated mechanisms to induce Tregs and enhance resolution of acute inflammation.