Proteolysis and class I major histocompatibility complex antigen presentation

Abstract

The class I major histocompatibility complex (MHC class I) presents 8-10 residue peptides to cytotoxic T lymphocytes. Most of these antigenic peptides are generated during protein degradation in the cytoplasm and are then transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP). Several lines of evidence have indicated that the proteasome is the major proteolytic activity responsible for generation of antigenic peptides--probably most conclusive has been the finding that specific inhibitors of the proteasome block antigen presentation. However, other proteases (e.g. the signal peptidase) may also generate some epitopes, particularly those on certain MHC class I alleles. The proteasome is responsible for generating the precise C termini of many presented peptides, and appears to be the only activity in cells that can make this cleavage. In contrast, aminopeptidases in the cytoplasm and endoplasmic reticulum can trim the N terminus of extended peptides to their proper size. Interestingly, the cellular content of proteases involved in the production and destruction of antigenic peptides is modified by interferon-gamma (IFN-gamma) treatment of cells. IFN-gamma induces the expression of three new proteasome beta subunits that are preferentially incorporated into new proteasomes and alter their pattern of peptidase activities. These changes are likely to enhance the yield of peptides with C termini appropriate for MHC binding and have been shown to enhance the presentation of at least some antigens. IFN-gamma also upregulates leucine aminopeptidase, which should promote the removal of N-terminal flanking residues of antigenic peptides. Also, this cytokine downregulates the expression of a metallo-proteinase, thimet oligopeptidase, that actively destroys many antigenic peptides. Thus, IFN-gamma appears to increase the supply of peptides by stimulating their generation and decreasing their destruction. The specificity and content of these various proteases should determine the amount of peptides available for antigen presentation. Also, the efficiency with which a peptide is presented is determined by the protein's half life (e.g. its ubiquitination rate) and the sequences flanking antigenic peptides, which influence the rates of proteolytic cleavage and destruction.

Quantitative modeling of peptide binding to TAP using support vector machine

“…SVM-Models trained using sparse sequence representation were selected. (A) Predictive performance (R p ) of SVM-models with regard to the fragment size used for training (1)(2)(3)(4)(5)(6)(7)(8)(9). Only the largest R p value achieved by a specific model (indicated in the abscissa) at each fragment size is represented.…”

“…3,4 Peptide fragments cleaved by proteasomes are shuttled to the lumen of the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP), where they can bind to newly assembling MHCI molecules. 5,6 Before MHCI binding, peptides can also undergo an optional N-terminal trimming by ER-associated amino peptidases (ERAAP). 7 Finally, peptide-MHCI complexes are exported to the cell surface for presentation to the CD8 T cells.…”

“…7 Finally, peptide-MHCI complexes are exported to the cell surface for presentation to the CD8 T cells. 5,6 There is evidence supporting that these processing steps limit/shape the peptides that can be presented by MHCI molecules in vivo, 7-9 thus explaining the numerous observations of high affinity MHCI binding peptides that are unable to elicit CTL responses. 10,11 Nonetheless, peptide transport by TAP represents the single most selective step in T cell epitope processing.…”

Immune Regulation and Evasion of Mammalian Host Cell Immunity During Viral Infection

“…Ultimately, the peptide loaded MHC-I complex is transported from the ER through Golgi to reach the cell surface, where they are recognised as epitopes by cytolytic T cells (CD8 ? T cells/CTLs) through their respective T cell receptors (TCR) to generate effector T cell response [31,53,118,144,146]. However, several virus-mediated immune evasion mechanisms are found to downregulate anti-viral immunity leading to defective antigen processing and presentation (Fig.…”

MHC Class II Allosteric Site Drugs: New Immunotherapeutics for Malignant, Infectious and Autoimmune Diseases*

“…A complete immune response to malignant and infectious diseases is thus effectively induced. MHC Class I molecules pick up antigenic peptides that have been transported into the ER by the transporter of antigenic peptides (TAP) after digestion and selection from cytoplasmic proteins by proteosomes [1,2]. The MHC Class I/ antigenic peptide complexes are recognized by CD8 1 cytotoxic T lymphocytes (CTLs).…”