Regulation of class I-restricted epitope processing by local or distal flanking sequence.

Yellen-Shaw, A J; Eisenlohr, Laurence C.

doi:10.4049/jimmunol.158.4.1727

Cited by 44 publications

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Promiscuous liberation of MHC-class I-binding peptides from the C termini of membrane and soluble proteins in the secretory pathway

et al. 1998

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TAP can efficiently transport peptides up to twice as long as those bound to MHC class I molecules, suggesting a role for endoplasmic reticulum (ER) proteases in the trimming of TAP-transported peptides. To better define ER processing of antigenic peptides, we examined the capacity of TAP-deficient cells to present determinants derived from ER-targeted proteins encoded by recombinant vaccinia viruses. TAP-deficient cells failed to present antigenic peptides from internal locations in secreted proteins to MHC class I-restricted T lymphocytes. The same peptides were liberated from the C termini of a secreted protein and the lumenal domains of two membrane proteins delivered to the ER via different routes. These findings suggest that proteases in the secretory compartment can liberate C-terminal antigenic peptides from virtually any context. We propose that this activity often participates in the removal of N-terminal extensions from TAP-transported peptides, thereby creating optimally sized products for MHC class I binding. We further demonstrate that ER trimming of C termini can occur if we express an appropriate carboxypeptidase in the secretory pathway. The absence of such trimming under normal circumstances suggests that carboxypeptidase activity is generally deficient in the ER, consistent with the concordance between the specificity of TAP and MHC class I molecules for the same types of C-terminal residues.

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Promiscuous liberation of MHC-class I-binding peptides from the C termini of membrane and soluble proteins in the secretory pathway

et al. 1998

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Effect of epitope flanking residues on the presentation of N-terminal cytotoxic T lymphocyte epitopes

et al. 1999

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We here demonstrate that placing two distinct influenza virus nucleoprotein epitopes at the N terminus of a cytosolic protein selectively blocks their presentation to specific cytotoxic T lymphocytes. The block is a cytosolic phenomenon, which can be overcome by distancing the epitope from the protein N terminus by two or more amino acids. Shortening the protein's C terminus fails to relieve the antigen presentation block. These results demonstrate that events at the N terminus of the target protein, rather than at its C terminus, are responsible for the lack of presentation of N‐terminal epitopes. We also show that lack of presentation of N terminal epitopes is associated with a modification of the target protein which affects its electrophoretic mobility and isoelectric focusing point. This modification can be prevented by mutating the epitope's N‐terminal flanking sequence, which results in an efficient presentation of the N‐terminal epitope. Lack of presentation of the N‐terminal epitopes results in a reduced ability of influenza‐primed mice to clear acute infection with vaccinia virus encoding an N‐terminal nucleoprotein epitope. Our results demonstrate that presentation of epitopes localized at the N terminus of cytosolic proteins can be modulated by events occurring at early stages of antigen processing.

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The presence of prolines in the flanking region of an immunodominant HIV‐2 gag epitope influences the quality and quantity of the epitope generated

et al. 2015

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Both the recognition of HIV‐infected cells and the immunogenicity of candidate CTL vaccines depend on the presentation of a peptide epitope at the cell surface, which in turn depends on intracellular antigen processing. Differential antigen processing maybe responsible for the differences in both the quality and the quantity of epitopes produced, influencing the immunodominance hierarchy of viral epitopes. Previously, we showed that the magnitude of the HIV‐2 gag‐specific T‐cell response is inversely correlated with plasma viral load, particularly when responses are directed against an epitope, 165DRFYKSLRA173, within the highly conserved Major Homology Region of gag‐p26. We also showed that the presence of three proline residues, at positions 119, 159 and 178 of gag‐p26, was significantly correlated with low viral load. Since this proline motif was also associated with stronger gag‐specific CTL responses, we investigated the impact of these prolines on proteasomal processing of the protective 165DRFYKSLRA173 epitope. Our data demonstrate that the 165DRFYKSLRA173 epitope is most efficiently processed from precursors that contain two flanking proline residues, found naturally in low viral‐load patients. Superior antigen processing and enhanced presentation may account for the link between infection with HIV‐2 encoding the “PPP‐gag” sequence and both strong gag‐specific CTL responses as well as lower viral load.

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Regulation of class I-restricted epitope processing by local or distal flanking sequence.

Cited by 44 publications

References 0 publications

Promiscuous liberation of MHC-class I-binding peptides from the C termini of membrane and soluble proteins in the secretory pathway

Promiscuous liberation of MHC-class I-binding peptides from the C termini of membrane and soluble proteins in the secretory pathway

Effect of epitope flanking residues on the presentation of N-terminal cytotoxic T lymphocyte epitopes

The presence of prolines in the flanking region of an immunodominant HIV‐2 gag epitope influences the quality and quantity of the epitope generated

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