The DOI matches its Crossref record; 26 of the 26 references it cites were found in a registry or an index.
A Single Autoimmune T Cell Receptor Recognizes More Than a Million Different Peptides
Open accessAbstract
The T cell receptor (TCR) orchestrates immune responses by binding to foreign peptides presented at the cell surface in the context of major histocompatibility complex (MHC) molecules. Effective immunity requires that all possible foreign peptide-MHC molecules are recognized or risks leaving holes in immune coverage that pathogens could quickly evolve to exploit. It is unclear how a limited pool of <10(8) human TCRs can successfully provide immunity to the vast array of possible different peptides that could be produced from 20 proteogenic amino acids and presented by self-MHC molecules (>10(15) distinct peptide-MHCs). One possibility is that T cell immunity incorporates an extremely high level of receptor degeneracy, enabling each TCR to recognize multiple peptides. However, the extent of such TCR degeneracy has never been fully quantified. Here, we perform a comprehensive experimental and mathematical analysis to reveal that a single patient-derived autoimmune CD8(+) T cell clone of pathogenic relevance in human type I diabetes recognizes >one million distinct decamer peptides in the context of a single MHC class I molecule. A large number of peptides that acted as substantially better agonists than the wild-type "index" preproinsulin-derived peptide (ALWGPDPAAA) were identified. The RQFGPDFPTI peptide (sampled from >10(8) peptides) was >100-fold more potent than the index peptide despite differing from this sequence at 7 of 10 positions. Quantification of this previously unappreciated high level of CD8(+) T cell cross-reactivity represents an important step toward understanding the system requirements for adaptive immunity and highlights the enormous potential of TCR degeneracy to be the causative factor in autoimmune disease.
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Regulatory T cells in cancer immunotherapy
Tanaka, A., & Sakaguchi, S. (2017) · Cell Research · doi:10.1038/cr.2016.151 · Cited by 1,860
Major Histocompatibility Complex Genomics and Human Disease
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Emerson, R. O., DeWitt, W. S., Vignali, M., Gravley, J., Hu, J. K., Osborne, E. J., Desmarais, C., Klinger, M., Carlson, C. S., Hansen, J. A., et al. (2017) · Nature Genetics · doi:10.1038/ng.3822 · Cited by 532
TCR-engineered T cell therapy in solid tumors: State of the art and perspectives
Baulu, E., Gardet, C., Chuvin, N., & Depil, S. (2023) · Science Advances · doi:10.1126/sciadv.adf3700 · Cited by 429
Gut Microbiota Regulation of T Cells During Inflammation and Autoimmunity
Brown, E. M., Kenny, D. J., & Xavier, R. J. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041841 · Cited by 312
Metadata
- Authors
- Wooldridge, L., Ekeruche-Makinde, J., van den Berg, H. A., Skowera, A., Miles, J. J., Tan, M. P., Dolton, G., Clement, M., Llewellyn-Lacey, S., Price, D. A., Peakman, M., & Sewell, A. K.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 287
- Issue
- 2
- Pages
- 1168-1177
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2157384708
- Cited by
- 455
- References
- 26
- FWCI
- 8.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Wooldridge, L., Ekeruche-Makinde, J., van den Berg, H. A., Skowera, A., Miles, J. J., Tan, M. P., Dolton, G., Clement, M., Llewellyn-Lacey, S., Price, D. A., Peakman, M., & Sewell, A. K. (2012). A Single Autoimmune T Cell Receptor Recognizes More Than a Million Different Peptides. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m111.289488
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