Autophagy and intracellular surveillance: Modulating MHC class II antigen presentation with stress
- Department of Microbiology and Immunology, Center for Immunobiology, and Walther Oncology Center, Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN 46202
MHC class I and II proteins selectively acquire peptides from self and foreign antigens for display to T lymphocytes. The spectrum of peptides displayed by class I and II proteins is critical for self-tolerance as well as the development of immunity against invasive pathogens and tumors. Traditionally, immunologists held that class I and II molecules were restricted in surveying distinct subcellular domains for ligands. With this model, endogenous antigens processed in the cytosol give rise to peptides for MHC class I presentation to cytotoxic T cells, whereas engulfed exogenous antigens degraded in endosomes and lysosomes are destined for MHC class II presentation to CD4+ T lymphocytes. However, alternative pathways for delivering exogenous antigens to MHC class I molecules have now been characterized (1). Similarly, biochemical and functional studies indicate that MHC class II molecules display peptides from cytoplasmic proteins for CD4+ T cell recognition with potential relevance to viral immunity, tumor immunity, and autoimmunity (2). Therefore, defining the specific mechanism(s) by which MHC class II molecules in endosomal and lysosomal compartments access peptides derived from intracellular antigens within the cytoplasm and nucleus has become a priority. Recent studies using specific viral and bacterial antigens as well as an autoantigen point to three possible pathways: bulk autophagy (3, 4), chaperone-mediated autophagy (5), and a TAP-dependent pathway (6). In this issue of PNAS, Dengjel et al. (7) take a different approach to this same problem, examining how the induction of autophagy alters the complex spectrum of peptides displayed by MHC class II molecules. Using serum starvation of human B-lymphoblasts to induce autophagy for different time periods, the authors demonstrate notable changes in the peptides associated with class II molecules. Remarkably, these authors also demonstrate that the induction of autophagy by starvation alters the balance of active proteases within lysosomes. …
