| Autor: |
Kelly JJ; Department of Chemistry University of Virginia Charlottesville, Virginia 22904, United States., Bloodworth N; Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical Center, Nashville, Tennessee 37240, United States., Shao Q; Department of Chemistry University of Virginia Charlottesville, Virginia 22904, United States., Shabanowitz J; Department of Chemistry University of Virginia Charlottesville, Virginia 22904, United States., Hunt D; Department of Chemistry University of Virginia Charlottesville, Virginia 22904, United States., Meiler J; Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical Center, Nashville, Tennessee 37240, United States.; Institute of Drug Discovery, Faculty of MedicineUniversity of Leipzig, Leipzig, SAC 04103, Germany.; Center for Structural Biology Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Chemistry Vanderbilt University, Nashville, Tennessee 37232, United States., Pires MM; Department of Chemistry University of Virginia Charlottesville, Virginia 22904, United States. |
| Abstrakt: |
The human major histocompatibility complex (MHC) plays a pivotal role in the presentation of peptidic fragments from proteins, which can originate from self-proteins or from nonhuman antigens, such as those produced by viruses or bacteria. To prevent cytotoxicity against healthy cells, thymocytes expressing T cell receptors (TCRs) that recognize self-peptides are removed from circulation (negative selection), thus leaving T cells that recognize nonself-peptides. Current understanding suggests that post-translationally modified (PTM) proteins and the resulting peptide fragments they generate following proteolysis are largely excluded from negative selection; this feature means that PTMs can generate nonself-peptides that potentially contribute to the development of autoreactive T cells and subsequent autoimmune diseases. Although it is well-established that PTMs are prevalent in peptides present on MHCs, the precise mechanisms by which PTMs influence the antigen presentation machinery remain poorly understood. In the present work, we introduce chemical modifications mimicking PTMs on synthetic peptides. This is the first systematic study isolating the impact of PTMs on MHC binding and also their impact on TCR recognition. Our findings reveal various ways PTMs alter antigen presentation, which could have implications for tumor neoantigen presentation. |
