Three-Dimensional Structure Determines the Pattern of CD4⁺T-Cell Epitope Dominance in Influenza Virus Hemagglutinin

Abstract

The structural context of a CD4؉ T-cell epitope is known to influence immunodominance at the level of antigen processing, but general rules have not emerged. Dominant epitopes of influenza virus hemagglutinin are found to be localized to the C-terminal flanks of conformationally stable segments identified by low crystallographic B-factors or high COREX residue stabilities. The bias toward C-terminal flanks is distinctive for antigens from the influenza virus. Dominant epitopes in antigens/allergens from other sources also localize to the flanks of stable segments but are found on either N-or C-terminal flanks. Thus, dominance arises from preferential endoproteolytic nicking between stable segments followed by loading of fragment terminal regions into antigen-presenting proteins. This mechanism probably arose in order to direct CD4 ؉ responses onto sequences that are conserved for structure and function. Structure-guided presentation could enhance protection against genetically drifting influenza virus variants but most likely reduces protection against new viral subtypes.

CD4+ T-cell epitope prediction using antigen processing constraints

“…The evaluation also excluded studies on mammalian antigens, for which some epitopes may have been suppressed by negative selection. Epitope maps of influenza antigens were excluded because epitope placement is exceptional, in that epitopes consistently appear on the N-terminal flanks of flexible sites, possibly due to viral modifications to antigen processing mechanisms [66]. The usefulness of excluding influenza epitopes highlights that fact that antigen-processing steps play an important role in shaping CD4+ epitope dominance.…”

Peptide Microarray-Based Identification of Mycobacterium tuberculosis Epitope Binding to HLA-DRB1*0101, DRB1*1501, and DRB1*0401

“…However, the fact that some of the identified peptides have been reported previously (3,26,27) using functional assays or tetramer-guided analysis (14) supports the validity of the approach reported here. It is also important to note that some of the candidate test peptides might not bind to the HLA-DR alleles in vivo due to differential protein processing and subsequent presentation: peptide processing is dependent on the three-dimensional structure of proteins (18,21,22,25). Future tetramer-guided analysis of PBMCs from patients with TB will aid in determining which peptides are presented in vivo and lead to expansion of antigen-specific CD4 ϩ T cells.…”

The effect of helper epitopes and cellular localization of an antigen on the outcome of gene gun DNA immunization

“…They should contain protease-sensitive sites accessible to digestion as described in the model of CD4 þ T-cell epitope generation and presentation. 16 For the p30 epitope, such flanking regions can be predicted from the data of the relative crystallographic B factor calculated for fragment H c of TT. 17 Thus, DNA vaccines derived from the E7GGG gene were modified not only with the sequence encoding p30 (aa 947-967, short form designated TT1s) but also with the enlarged sequence carrying potential protease-cleavege sites (aa 936-975, long form TT1l).…”