Cutting edge: MHC class II-restricted peptides containing the inflammation-associated marker 3-nitrotyrosine evade central tolerance and elicit a robust cell-mediated immune response.
Nitrotyrosine is widely recognized as a surrogate marker of up-regulated inducible NO synthase expression at sites of inflammation. However, the potential immunogenicity of autologous proteins containing nitrotyrosine has not previously been investigated. Herein, we used the I-E(K)-restricted T cell epitope of pigeon/moth cytochrome c (PCC/MCC(88-103)) to assess the ability of T cells to recognize ligands containing nitrotyrosine. Substitution of the single tyrosine (Y97) in PCC/MCC(88-103) with nitrotyrosine abrogates recognition by the MCC(88-103)-specific T cell hybridoma 2B4. CBA (H2(K)) mice immunized with MCC(88-103) or nitrated MCC(88-103) peptides produce T cell responses that are mutually exclusive. Transgenic mice that constitutively express PCC under the control of an MHC class I promoter are tolerant toward immunization with MCC(88-103), but exhibited a robust immune response against nitrated MCC(88-103). Analysis of T cell hybridomas specific for nitrated-MCC(88-103) indicated that subtle differences in TCR VDJ gene usage are sufficient to allow nitrotyrosine-specific T cells to escape the processes of central tolerance.
Birnboim
H Chaim
HC
Ottawa Regional Cancer Center, University of Ottawa, Ottawa, Canada.
Lemay
Anne-Marie
AM
Lam
Debbie Ka Yee
DK
Goldstein
Rose
R
Webb
John R
JR
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D016466:CHO Cells; D002460:Cell Line; D010856:Columbidae; D006224:Cricetinae; D003574:Cytochrome c Group / Q000008:administration & dosage / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009036:Moths; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000276:immunology* / Q000378:metabolism
D001324:Autoantigens; D003574:Cytochrome c Group; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D018836:Inflammation Mediators; D010455:Peptides; C002744:3-nitrotyrosine; D014443:Tyrosine