Yewdell et al. summarize multiple sources of data and speculate on a fundamental question of adaptive immunity – how does the antigen processing machinery of the cell efficiently distinguish and highlight new and potentially dangerous genetic information from the vast extant transcriptome/proteome of the cell? Drawing on known examples of non-canonical translation and peptide presentation (CUG initiation, UTR and lncRNA open reading frames, nuclear translation), DRiPs, ribosome alterations, and examples of formation of compartmentalized cell “organelles”, Yewdell et al. synthesize testable hypotheses and pose key outstanding questions.
MHC class I presentation of short peptides enables CD8(+) T cell (TCD8+) immunosurveillance of tumors and intracellular pathogens. A key feature of the class I pathway is that the immunopeptidome is highly skewed from the cellular degradome, indicating high selectivity of the access of protease-generated peptides to class I molecules. Similarly, in professional antigen-presenting cells, peptides from minute amounts of proteins introduced into the cytosol outcompete an overwhelming supply of constitutively generated peptides. Here, we propose that antigen processing is based on substrate channeling and review recent studies from the antigen processing and cell biology fields that provide a starting point for testing this hypothesis.
Author Info: (1) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD 20892, USA. Electronic address: jyewdell@niaid.nih.gov. (2) Laboratory
Author Info: (1) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD 20892, USA. Electronic address: jyewdell@niaid.nih.gov. (2) Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD 20892, USA. (3) Inserm, 27 rue Juliette Dodu, 750 10 Paris, France; International Centre for Cancer Vaccine Science (ICCVS), University of Gdansk, Science, ul. Wita Stwosza 63, 80-308 Gdansk, Poland; Department of Medical Biosciences, Umea University, 90187 Umea, Sweden; RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 65653 Brno, Czech Republic.
