Journal
BIOCHEMISTRY
Volume 61, Issue 15, Pages 1585-1599Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.2c00237
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Funding
- National Institutes of Health (NIH) [R21-AI122199, U54 CA260581, P20 RR018766, P20 GM103514, P30 GM103514]
- Louisiana State University School of Medicine Office of the Dean
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Antigen processing in the class II MHC pathway depends on proteolytic enzymes and the competition among antigen folding, proteolysis, and MHCII binding leads to CD4+ epitope dominance. Using X-ray crystal structures, antigen processing likelihood (APL) can accurately predict CD4+ epitopes. Crystal structure analysis can also capture the role of antigen structure in proteolysis.
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 among antigen folding, proteolysis, and MHCII binding. Protease-sensitive sites, linear antibody epitopes, and CD4+ T-cell epitopes were mapped in 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 for F1-V without considering peptide-MHCII binding affinity. We also show that APL achieves excellent performance over two benchmark antigen sets. 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, MHCII binding, or both. For a sample of 13 diverse antigens, the accuracy of epitope prediction by the combination of APL and I-Ab-MHCII-peptide affinity reached 36%. When MHCII allele specificity was also diverse, such as in human immunity, prediction of dominant epitopes by APL alone reached 42% when using a stringent scoring threshold. Because 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.
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