2017 in nearly upon us, but the Heit lab was able to squeeze out one last paper in 2016. This is an exciting moment for our lab, as this study was the major focus of our work for nearly five years. Our goal in this study was to understand how macrophages decide how to respond to the different types of targets they encounter in tissues. This decision-making process is coordinated by Rab17, which selectively diverts non-infectious materials away from parts of the macrophage used to initiate anti-pathogen immune responses.
This decision making process is a key function of macrophages, as these cells are tasked with both “housekeeping duties” (e.g. removing the dead and dying cells that form normally in our bodies) and with anti-pathogen defence. Both dying self-cells and pathogens are internalized and degraded by macrophages, and it is at this point that macrophages need to make a key decision – whether to present these degraded materials to other immune cells, thus activating a broader immune response. Making this decision correctly is critically important as presenting degraded self-cells to your immune system may lead to an autoimmune disease such as multiple sclerosis or rheumatoid arthritis, whereas failing to present a degraded pathogen may enable infection.
How this “decision” is made was not clear – until now. By recovering macrophage vacuoles containing beads which mimicked either dead cells or pathogens, and then using mass spectrometry to identify the proteins present on each vacuole, we were able to identify the protein Rab17 as a protein selectively recruited to the dead cell-containing vacuole. Microscopy-based studies then determined that this protein directs degraded dead cell materials to an organelle called the “recycling endosome”, where that material is either absorbed or expelled by the macrophage. Rab17 does not accumulate on pathogen-containing vacuoles, thereby preventing recycling of degraded pathogens. Instead, degraded pathogens are trafficked to a different organelle, where they are loaded on the MHC II molecules that present the degraded pathogen to the immune system.