Oxidative stress can alter the antigenicity of immunodominant peptides.
APCs operate frequently under oxidative stress induced by aging, tissue damage, pathogens, or inflammatory responses. Phagocytic cells produce peroxides and free-radical species that facilitate pathogen clearance and can in the case of APCs, also lead to oxidative modifications of antigenic proteins and peptides. Little information is available presently about the consequences of such modifications on the immune response. To model oxidative modification of an immunodominant antigenic peptide, we oxidized the methionine residue of the human CMV pp65(495-503) (NLVPMVATV) peptide. Such modifications of an antigenic peptide can affect MHC binding or TCR recognition. Using binding and dissociation assays, we demonstrate that oxidative modification of the CMVpp65(495-503) peptide leads to a decreased binding of the pMHC complex to the TCR, whereas binding of the peptide to the MHC class I molecule is not impaired. Additionally, we show that CD8(+) T cells have a decreased proliferation and IFN-gamma production when stimulated with oxidized CMVpp65(495-503) peptide. Spectratyping the antigen-binding site of the TCR of responding T cells demonstrates that the CMVpp65(495-503) and the CMVoxpp65(495-503) peptides preferentially stimulate BV8 T cells. Sequencing of this dominant BV family reveals a highly conserved CDR3 amino acid motif, independent of the mode of stimulation, demonstrating the recruitment of the same T cell clonotypes. Our results suggest that oxidative modification of antigenic peptides may affect T cell responses severely by binding T cell clones with different affinity. This may lead to an altered immune response against infectious agents as well as against tumor or autoantigens under oxidative stress conditions.
Austrian Academy of Sciences, Rennweg 10, 6020 Innsbruck, Austria.
Daniela
D
Weiskopf
Angelika
A
Schwanninger
Birgit
B
Weinberger
Giovanni
G
Almanzar
Walther
W
Parson
Soren
S
Buus
Herbert
H
Lindner
Beatrix
B
Grubeck-Loebenstein
D000328:Adult; D020816:Amino Acid Motifs; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000956:Antigens, Viral / Q000737:chemistry / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology; D005260:Female; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016056:Immunodominant Epitopes / Q000187:drug effects / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D008715:Methionine / Q000737:chemistry; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D010750:Phosphoproteins / Q000737:chemistry / Q000187:drug effects / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000187:drug effects / Q000276:immunology*
D000956:Antigens, Viral; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D010750:Phosphoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D007371:Interferon-gamma; D008715:Methionine; D006861:Hydrogen Peroxide