Apoptotic cells (ACs) cleared by phagocytosis are routinely able to evade stimulating an anti-self immune response despite harboring numerous self-antigens. After demonstrating that ACs did not affect VEGF-A, Arg2, costimulatory CD28, or coinhibitory PD-L1 or PD-L2, Yakoub et al. uncovered that apoptotic cells induce the upregulation of coinhibitory ligand CD80 on macrophages mildly upon cell-cell recognition, and strongly upon phagocytosis of the ACs, thus suppressing T cell activation. This effect was specific to ACs (not observed with necrotic cells), and was independent of the concentration and cell type of the apoptotic cells.
Apoptosis is an important physiological process in development and disease. Apoptotic cells (ACs) are a major source of self-antigens, but ACs usually evade immune responses. The mechanism by which ACs repress T cell adaptive immune responses is poorly understood. T cell activation is finely regulated by a balance of costimulatory signaling (mediated by the costimulatory receptor CD28 on T cells) and coinhibitory signaling (mediated by the coinhibitory ligands CD80 and PD-L1 and -2 on Antigen-Presenting Cells). Here, we found that ACs specifically upregulated the coinhibitory ligand CD80 on macrophages. Conversely, ACs did not exhibit a robust regulation of the other coinhibitory ligands on macrophages or the costimulatory receptor CD28 on T cells. We show that the robust positive regulation of CD80 by ACs requires phagocytosis of ACs by macrophages. We also demonstrate that CD80 modulation by dead cells is a specific effect of ACs, but not necrotic cells (which stimulate immune responses). These results indicate that ACs modulate the coinhibitory pathway of T cell activation via CD80, and suggest a role for CD80 in suppressing T cell responses by ACs. Understanding a mechanism of regulating adaptive immune responses to ACs, which harbor an abundance of self-antigens, may advance our understanding of mechanisms of regulating autoimmunity and facilitate future therapy development for autoimmune disorders.
Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford University, Stanford, CA, 94305, USA. abraam@stanford.edu. (2) Division of Mol
Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford University, Stanford, CA, 94305, USA. abraam@stanford.edu. (2) Division of Molecular Genetics, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. (3) Division of Molecular Genetics, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Heidelberg, Germany. (4) Department of Pharmaceutical Biotechnology, University of Illinois College of Pharmacy, Chicago, IL, 60612, USA. Department of Research and Development, Akorn Pharmaceuticals, Vernon Hills, IL, 60061, USA.
