Alpha (v) integrins license regulatory T cells to apoptotic cells and self-associated antigens

Abstract

Defects in apoptotic cell clearance are thought to contribute to autoimmunity by failure to induce tolerance, coupled with accumulation of immunogenic material. However, little is known about the contribution of apoptosis to immune responses at mucosal sites, where regulatory T cells (T(reg) cells) and other immune cells play an essential active role in maintaining tolerance to self-associated antigens. In recent studies, we have found that α(v) integrins have an important role in apoptotic cell phagocytosis and induction of T(reg) cells in the intestine, and deletion of α(v) from myeloid cells causes colitis associated with failed apoptotic cell removal and loss of T(reg) cells. Our data show that activation of transforming growth factor (TGF)-β by α(v) β(8) on dendritic cells (DCs) is essential for generating T(reg) cells and inducing mucosal tolerance. These results provide a mechanism by which tolerance to apoptotic cell-derived and -associated antigens is maintained by DC "licensing" at sites of high TGF-β expression.