T cell repertoire to citrullinated self-peptides in healthy humans is not confined to the HLA-DR SE alleles; targeting of citrullinated self-peptides presented by HLA-DP4 for tumour therapy

Brentville, Victoria; Symonds, Peter; Cook, Katherine W.; Daniels, Ian; Pitt, Tracy; Gijon, Mohamed; Vaghela, Poonam; Xue, Wei; Shah, Sabaria; Metheringham, Rachael L.; Durrant, Lindy G.

Abstract

Post-translational modifications are induced in stressed cells which cause them to be recognised by the immune system. One such modification is citrullination where the positive charged arginine is modified to a neutral citrulline. We demonstrate most healthy donors show an oligoclonal CD4 response in vitro to at least one citrullinated vimentin or enolase peptide. Unlike rheumatoid arthritis patients, these T cell responses were not restricted by HLA-DRB1 shared epitope (SE) alleles, suggesting they could be presented by other MHC-II alleles. As HLA-DP is less polymorphic than HLA-DR, we investigated whether the common allele, HLA-DP4 could present citrullinated epitopes. The modification of arginine to citrulline enhanced binding of the peptides to HLA-DP4 and induced high frequency CD4 responses in HLA-DP4 transgenic mouse models. Our previous studies have shown that tumours present citrullinated peptides restricted through HLA-DR4 which are good targets for anti-tumour immunity. In this study we show that citrullinated vimentin and enolase peptides also induced strong anti-tumour immunity (100% survival, p

Citation

Brentville, V., Symonds, P., Cook, K. W., Daniels, I., Pitt, T., Gijon, M., Vaghela, P., Xue, W., Shah, S., Metheringham, R. L., & Durrant, L. G. (2019). T cell repertoire to citrullinated self-peptides in healthy humans is not confined to the HLA-DR SE alleles; targeting of citrullinated self-peptides presented by HLA-DP4 for tumour therapy. OncoImmunology, 8(5), Article e1576490. https://doi.org/10.1080/2162402X.2019.1576490

• Journal Article Type: Article
• Acceptance Date: Dec 11, 2018
• Online Publication Date: Feb 20, 2019
• Publication Date: Feb 20, 2019
• Deposit Date: Jan 7, 2019
• Publicly Available Date: Feb 21, 2020
• Journal: OncoImmunology
• Print ISSN: 2162-4011
• Electronic ISSN: 2162-402X
• Publisher: Taylor and Francis
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 5
• Article Number: e1576490
• DOI: https://doi.org/10.1080/2162402X.2019.1576490
• Keywords: Immunology; Immunology and Allergy; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/1446751
• Publisher URL: https://www.tandfonline.com/doi/full/10.1080/2162402X.2019.1576490
• Additional Information: This is an Accepted Manuscript of an article published by Taylor & Francis in OncoImmunology on 12 Feb 2019, available online: https://doi.org/10.1080/2162402X.2019.1576490.
• Contract Date: Jan 7, 2019