Leucine aminopeptidase is not essential for trimming peptides in the cytosol or generating epitopes for MHC class I antigen presentation.
To detect viral infections and tumors, CD8+ T lymphocytes monitor cells for the presence of antigenic peptides bound to MHC class I molecules. The majority of MHC class I-presented peptides are generated from the cleavage of cellular and viral proteins by the ubiquitin-proteasome pathway. Many of the oligopeptides produced by this process are too long to stably bind to MHC class I molecules and require further trimming for presentation. Leucine aminopeptidase (LAP) is an IFN-inducible cytosolic aminopeptidase that can trim precursor peptides to mature epitopes and has been thought to play an important role in Ag presentation. To examine the role of LAP in generating MHC class I peptides in vivo, we generated LAP-deficient mice and LAP-deficient cell lines. These mutant mice and cells are viable and grow normally. The trimming of peptides in LAP-deficient cells is not reduced under basal conditions or after stimulation with IFN. Similarly, there is no reduction in presentation of peptides from precursor or full-length Ag constructs or in the overall supply of peptides from cellular proteins to MHC class I molecules even after stimulation with IFN. After viral infection, LAP-deficient mice generate normal CTL responses to seven epitopes from three different viruses. These data demonstrate that LAP is not an essential enzyme for generating most MHC class I-presented peptides and reveal redundancy in the function of cellular aminopeptidases.
Towne
Charles F
CF
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
York
Ian A
IA
Neijssen
Joost
J
Karow
Margaret L
ML
Murphy
Andrew J
AJ
Valenzuela
David M
DM
Yancopoulos
George D
GD
Neefjes
Jacques J
JJ
Rock
Kenneth L
KL
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007931:Leucyl Aminopeptidase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology; D014162:Transfection; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology
D000956:Antigens, Viral; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D034741:RNA, Small Interfering; D007931:Leucyl Aminopeptidase