Regulation of peptide presentation by major histocompatibility complex class II molecules at the surface of macrophages.
We studied major histocompatibility complex class II-dependent presentation of two T cell epitopes delivered as synthetic peptides by fixed macrophages. Treatment of bone marrow macrophages with inhibitors of proteinases of the metallo-, aspartic and serine proteinase families enhanced presentation of peptides, indicating that several enzyme families participate in destructive antigen processing of exogenous peptides. High performance liquid chromatography and mass spectrometry analysis demonstrated the presence of peptide fragments in macrophage supernatants, and permitted identification of the cleavage sites which confirmed the enzyme families involved. Peptide fragments were shown to be competitive inhibitors of presentation of the full-length peptide to CD4 T cells by fixed and live macrophages. The results indicate that several classes of proteinases can modulate antigen presentation by at least two mechanisms: (1) degradation of extracellular oligopeptides and (2) generation of natural peptide ligands that block antigen presentation to CD4 T cells. The generation of inhibitory natural peptide ligands is a new mechanism of immunoregulation which could operate during the induction of T cell responses in a variety of situations.
von Delwig
Alexei
A
Musculoskeletal Research Group, School of Clinical Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, GB. alexi.delvig@ncl.ac.uk
Musson
Julie A
JA
McKie
Norman
N
Gray
Joe
J
Robinson
John H
JH
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D015842:Serine Proteinase Inhibitors; D001619:beta-N-Acetylhexosaminidases