Immune responses to citrullinated and homocitrullinated peptides in healthy donors are not restricted to the HLA SE shared allele and can be selected into the memory pool.

Autor: Choudhury RH; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Daniels I; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Vaghela P; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Atabani S; Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK., Kirk T; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Symonds P; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Cook KW; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Al-Omari A; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Weston D; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Shah S; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Hutchinson D; Royal Cornwall Hospitals NHS Trust, Truro, Cornwall, UK., Paston SJ; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Metheringham RL; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Brentville VA; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK., Durrant LG; Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, UK.; Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham, UK.
Jazyk: angličtina
Zdroj: Immunology [Immunology] 2023 Aug; Vol. 169 (4), pp. 467-486. Date of Electronic Publication: 2023 Apr 13.
DOI: 10.1111/imm.13645
Abstrakt: Citrullination and homocitrullination are stress induced post-translational modifications (siPTMs) which can be recognized by T cells. Peripheral blood mononuclear cells isolated from healthy donors and rheumatoid arthritis (RA) patients were stimulated with nine siPTM-peptides. CD45RA/CD45RO depletion was employed to determine if peptide-specific responses are naïve or memory. Human leucocyte antigen (HLA)-DP4 and HLA-DR4 transgenic mice were immunized with siPTM-peptides and immune responses were determined with ex vivo ELISpot assays. The majority (24 out of 25) of healthy donors showed CD4 T cell-specific proliferation to at least 1 siPTM-peptide, 19 to 2 siPTM-peptides, 14 to 3 siPTM-peptides, 9 to 4 siPTM-peptides, 6 to 5 siPTM-peptides and 4 to 6 siPTM-peptides. More donors responded to Vim28-49cit (68%) and Bip189-208cit (75%) compared with Vim415-433cit (33%). In RA patients, the presentation of citrullinated epitopes is associated with HLA-SE alleles; however, we witnessed responses in healthy donors who did not express the SE allele. The majority of responding T cells were effector memory cells with a Th1/cytotoxic phenotype. Responses to Vim28-49cit and Eno241-260cit originated in the memory pool, while the response to Vim415-433cit was naïve. In the HLA-DP4 and HLA-DR4 transgenic models, Vim28cit generated a memory response. Peptide-specific T cells were capable of Epstein-Barr virus transformed lymphoblastoid cell line recognition suggesting a link with stress due to infection. These results suggest siPTM-peptides are presented under conditions of cellular stress and inflammation and drive cytotoxic CD4 T cell responses that aid in the removal of stressed cells. The presentation of such siPTM-peptides is not restricted to HLA-SE in both humans and animal models.
(© 2023 Scancell and The Authors. Immunology published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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