Endoplasmic reticulum aminopeptidase associated with antigen processing defines the composition and structure of MHC class I peptide repertoire in normal and virus-infected cells.
The MHC class I (MHC-I) molecules ferry a cargo of peptides to the cell surface as potential ligands for CD8(+) cytotoxic T cells. For nearly 20 years, the cargo has been described as a collection of short 8-9 mer peptides, whose length and sequences were believed to be primarily determined by the peptide-binding groove of MHC-I molecules. Yet the mechanisms for producing peptides of such optimal length and composition have remained unclear. In this study, using mass spectrometry, we determined the amino acid sequences of a large number of naturally processed peptides in mice lacking the endoplasmic reticulum aminopeptidase associated with Ag processing (ERAAP). We find that ERAAP-deficiency changed the oeuvre and caused a marked increase in the length of peptides normally presented by MHC-I. Furthermore, we observed similar changes in the length of viral peptides recognized by CD8(+) T cells in mouse CMV-infected ERAAP-deficient mice. In these mice, a distinct CD8(+) T cell population was elicited with specificity for an N-terminally extended epitope. Thus, the characteristic length, as well as the composition of MHC-I peptide cargo, is determined not only by the MHC-I peptide-binding groove but also by ERAAP proteolysis in the endoplasmic reticulum.
Blanchard
Nicolas
N
Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Kanaseki
Takayuki
T
Escobar
Hernando
H
Delebecque
Frédéric
F
Nagarajan
Niranjana A
NA
Reyes-Vargas
Eduardo
E
Crockett
David K
DK
Raulet
David H
DH
Delgado
Julio C
JC
Shastri
Nilabh
N
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000821:virology; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000276:immunology* / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D064532:Histocompatibility Antigen H-2D; D006825:Hybridomas; D006868:Hydrolysis; D007931:Leucyl Aminopeptidase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018146:Muromegalovirus / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D053719:Tandem Mass Spectrometry; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D010446:Peptide Fragments; D014764:Viral Proteins; D007931:Leucyl Aminopeptidase; C456799:puromycin-insensitive leucyl-specific aminopeptidase