Abstract
Major histocompatibility class I (MHC-I) proteins mediate immunosurveillance against pathogens and cancers by presenting antigenic or mutated peptides to antigen receptors of CD8+ T cells and by engaging receptors of natural killer (NK) cells. In humans, MHC-I molecules are highly polymorphic. MHC-I variations permit the display of thousands of distinct peptides at the cell surface. Recent mass spectrometric studies have revealed unique and shared characteristics of the peptidomes of individual MHC-I variants. The cell surface expression of MHC-I–peptide complexes requires the functions of many intracellular assembly factors, including the transporter associated with antigen presentation (TAP), tapasin, calreticulin, ERp57, TAP-binding protein related (TAPBPR), endoplasmic reticulum aminopeptidases (ERAPs), and the proteasomes. Recent studies provide important insights into the structural features of these factors that govern MHC-I assembly as well as the mechanisms underlying peptide exchange. Conformational sensing of MHC-I molecules mediates the quality control of intracellular MHC-I assembly and contributes to immune recognition by CD8 at the cell surface. Recent studies also show that several MHC-I variants can follow unconventional assembly routes to the cell surface, conferring selective immune advantages that can be exploited for immunotherapy.
Highlights
Major histocompatibility class I (MHC-I) proteins are expressed on the cell surface of nucleated cells and serve critical functions in the immune response by mediating the activation of CD8+ T cells and regulating the activity of natural killer (NK) cells
Recent studies focused on the evaluation of a therapeutic model that involved the use of targeted knockdown of transporter associated with antigen presentation (TAP) in tumor cells to enhance the efficacy of conventionally used checkpoint inhibitors and to test the potential of TEIPP-based peptide vaccines in cancer therapy[72,73]
Summary Human MHC-I molecules are highly polymorphic with specific peptide motif preferences that are being visualized in expanding numbers, which allow more accurate predictions of peptide repertoire sizes and antigenic epitopes
Summary
Major histocompatibility class I (MHC-I) proteins are expressed on the cell surface of nucleated cells and serve critical functions in the immune response by mediating the activation of CD8+ T cells and regulating the activity of natural killer (NK) cells. Some allotypes have more efficient HLA-I assembly and surface expression under TAP-deficient conditions than others because those HLA-I molecules bind peptides that are better represented within signal sequences or protein transmembrane domains, allowing higher levels of peptide access in the ER lumen independently of TAP33,45. T cells against an epitope derived from the leader sequence of LDL receptor-associated protein 1 (LRPAP1) are shown to recognize TAP-deficient tumor cells of different histological origins, but not healthy cells[71] Based on these findings, recent studies focused on the evaluation of a therapeutic model that involved the use of targeted knockdown of TAP in tumor cells to enhance the efficacy of conventionally used checkpoint inhibitors and to test the potential of TEIPP-based peptide vaccines in cancer therapy[72,73].
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