CD4+ T-Cell Epitope Prediction by Combined Analysis of Antigen Conformational Flexibility and Peptide-MHCII Binding Affinity
| Autor: | Daniel L. Moss, Samuel J. Landry, Kummer A Nicholas, Tysheena P. Charles, Pawan Bhat, Avik Bhattacharya, Ramgopal R. Mettu, Peyton W Moore |
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| Rok vydání: | 2022 |
| Předmět: |
CD4-Positive T-Lymphocytes
biology Protein Conformation Chemistry Antigen processing Proteolytic enzymes Epitopes T-Lymphocyte Peptide binding Major histocompatibility complex Biochemistry Epitope Cell biology Mice Inbred C57BL Mice Antigen Mice Inbred CBA biology.protein Animals Humans LcrV Antibody Peptides Peptide Hydrolases |
| Zdroj: | Biochemistry. 61:1585-1599 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/acs.biochem.2c00237 |
| Popis: | Antigen processing in the class II MHC pathway depends on conventional proteolytic enzymes, potentially acting on antigens in native-like conformational states. CD4+ epitope dominance arises from a competition between antigen folding, proteolysis, and MHCII binding. Protease-sensitive sites, linear antibody epitopes, and CD4+ T-cell epitopes were mapped in the plague vaccine candidate F1-V to evaluate the various contributions to CD4+ epitope dominance. Using X-ray crystal structures, antigen processing likelihood (APL) predicts CD4+ epitopes with significant accuracy without considering peptide-MHCII binding affinity. The profiles of conformational flexibility derived from the X-ray crystal structures of the F1-V proteins, Caf1 and LcrV, were similar to the biochemical profiles of linear antibody epitope reactivity and protease-sensitivity, suggesting that the role of structure in proteolysis was captured by the analysis of the crystal structures. The patterns of CD4+ T-cell epitope dominance in C57BL/6, CBA, and BALB/c mice were compared to epitope predictions based on APL, peptide binding to MHCII proteins, or both. For a sample of 13 diverse antigens larger than 200 residues, accuracy of epitope prediction by the combination of APL and I-Ab-MHCII-peptide affinity approached 40%. When MHCII allele specificity is also diverse, such as in human immunity, prediction of dominant epitopes by APL alone approached 40%. Since dominant CD4+ epitopes tend to occur in conformationally stable antigen domains, crystal structures typically are available for analysis by APL; and thus, the requirement for a crystal structure is not a severe limitation. |
| Databáze: | OpenAIRE |
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