KIM ‐1‐/ TIM ‐1‐mediated phagocytosis links ATG 5‐/ ULK 1‐dependent clearance of apoptotic cells to antigen presentation

Abstract

Phagocytosis of apoptotic cells by both professional and semi‐professional phagocytes is required for resolution of organ damage and maintenance of immune tolerance. KIM ‐1/ TIM ‐1 is a phosphatidylserine receptor that is expressed on epithelial cells and can transform the cells into phagocytes. Here, we demonstrate that KIM ‐1 phosphorylation and association with p85 results in encapsulation of phagosomes by lipidated LC 3 in multi‐membrane organelles. KIM ‐1‐mediated phagocytosis is not associated with increased ROS production, and NOX inhibition does not block LC 3 lipidation. Autophagy gene expression is required for efficient clearance of apoptotic cells and phagosome maturation. KIM ‐1‐mediated phagocytosis leads to pro‐tolerogenic antigen presentation, which suppresses CD 4 T‐cell proliferation and increases the percentage of regulatory T cells in an autophagy gene‐dependent manner. Taken together, these data reveal a novel mechanism of epithelial biology linking phagocytosis, autophagy and antigen presentation to regulation of the inflammatory response. image This study reveals how KIM ‐1/ TIM ‐1‐mediated phagocytosis down‐modulates inflammation through ATG 5 and ULK 1‐dependent autophagic processing of phagocytosed material to MHC I and MHC II . Phagocytosis of apoptotic cells by KIM ‐1, a non‐myeloid phagocytosis receptor, induces LC 3 lipidation of resulting phagosomes. Autophagy protein expression, ATG 5, ULK 1 and Beclin1, are required for LC 3 targeting to phagosomes and efficient phagosome acidification and maturation. KIM ‐1 signaling via the PI 3 kinase subunit p85 promotes LC 3 lipidation and accumulation on phagosomes. Phagocytosed material processed through autophagy is presented to MHC I and MHC II . Enhanced antigen presentation resulting from autophagic processing results in a pro‐tolerogenic milieu, reducing the percentage of CD 4 effector T cells while increasing the percentage of regulatory T cells.