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The Journal of Immunology, 2003, 171: 528-532.
Copyright © 2003 by The American Association of Immunologists

CUTTING EDGE

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 1

H. Chaim Birnboim*,¶, Anne-Marie Lemay{dagger}, Debbie Ka Yee Lam{dagger}, Rose Goldstein{ddagger},§ and John R. Webb2,{dagger},¶

* Ottawa Regional Cancer Center, {dagger} Department of Biochemistry, Microbiology and Immunology, University of Ottawa, {ddagger} Ottawa Hospital Research Institute, § Division of Rheumatology, Department of Medicine, University of Ottawa, Novasante Corp., Ottawa, Canada

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-EK-restricted T cell epitope of pigeon/moth cytochrome c (PCC/MCC88–103) to assess the ability of T cells to recognize ligands containing nitrotyrosine. Substitution of the single tyrosine (Y97) in PCC/MCC88–103 with nitrotyrosine abrogates recognition by the MCC88–103-specific T cell hybridoma 2B4. CBA (H2K) mice immunized with MCC88–103 or nitrated MCC88–103 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 MCC88–103, but exhibited a robust immune response against nitrated MCC88–103. Analysis of T cell hybridomas specific for nitrated-MCC88–103 indicated that subtle differences in TCR VDJ gene usage are sufficient to allow nitrotyrosine-specific T cells to escape the processes of central tolerance.




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