PMID- 37686141 OWN - NLM STAT- MEDLINE DCOM- 20230911 LR - 20230918 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 17 DP - 2023 Aug 28 TI - ERAP1 and ERAP2 Haplotypes Influence Suboptimal HLA-B*27:05-Restricted Anti-Viral CD8+ T Cell Responses Cross-Reactive to Self-Epitopes. LID - 10.3390/ijms241713335 [doi] LID - 13335 AB - The human leukocyte antigen (HLA)-B*27 family of alleles is strongly associated with ankylosing spondylitis (AS), a chronic inflammatory disorder affecting the axial and peripheral joints, yet some HLA-B*27 variants not associated with AS have been shown. Since no major differences in the ligandome of associated compared to not-associated alleles have emerged, a plausible hypothesis is that the quantity rather than the quality of the presented epitopes makes the difference. In addition, the Endoplasmic Reticulum AminoPeptidases (ERAPs) 1 and 2, playing a crucial role in shaping the HLA class I epitopes, act as strong AS susceptibility factors, suggesting that an altered peptidome might be responsible for the activation of pathogenic CD8+ T cells. In this context, we have previously singled out a B*27:05-restricted CD8+ T cell response against pEBNA3A (RPPIFIRRL), an EBV peptide lacking the B*27 classic binding motif. Here, we show that a specific ERAP1/2 haplotype negatively correlates with such response in B*27:05 subjects. Moreover, we prove that the B*27:05 allele successfully presents peptides with the same suboptimal N-terminal RP motif, including the self-peptide, pDYNEIN (RPPIFGDFL). Overall, this study underscores the cooperation between the HLA-B*27 and ERAP1/2 allelic variants in defining CD8+ T cell reactivity to suboptimal viral and self-B*27 peptides and prompts further investigation of the B*27:05 peptidome composition. FAU - Tedeschi, Valentina AU - Tedeschi V AD - Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy. FAU - Paldino, Giorgia AU - Paldino G AD - Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy. FAU - Alba, Josephine AU - Alba J AUID- ORCID: 0000-0002-5467-4751 AD - Department of Biology, University of Fribourg, Chemin du Musee, 1700 Fribourg, Switzerland. FAU - Molteni, Emanuele AU - Molteni E AD - Rheumatology Unit, Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy. FAU - Paladini, Fabiana AU - Paladini F AUID- ORCID: 0000-0003-1040-452X AD - Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy. FAU - Scrivo, Rossana AU - Scrivo R AUID- ORCID: 0000-0002-2889-8962 AD - Rheumatology Unit, Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy. FAU - Congia, Mattia AU - Congia M AD - Rheumatology Unit, AOU and University of Cagliari, 09042 Monserrato, Italy. FAU - Cauli, Alberto AU - Cauli A AD - Rheumatology Unit, AOU and University of Cagliari, 09042 Monserrato, Italy. FAU - Caccavale, Rosalba AU - Caccavale R AD - Department of Biotechnology and Medical Surgical Sciences, Division of Clinical Immunology and Rheumatology, Sapienza University of Rome c/o Polo Pontino, 04100 Latina, Italy. FAU - Paroli, Marino AU - Paroli M AUID- ORCID: 0000-0001-7919-9128 AD - Department of Biotechnology and Medical Surgical Sciences, Division of Clinical Immunology and Rheumatology, Sapienza University of Rome c/o Polo Pontino, 04100 Latina, Italy. FAU - Di Franco, Manuela AU - Di Franco M AUID- ORCID: 0000-0002-5468-2065 AD - Rheumatology Unit, Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Policlinico Umberto I, Sapienza University of Rome, 00161 Rome, Italy. FAU - Tuosto, Loretta AU - Tuosto L AUID- ORCID: 0000-0001-9056-4077 AD - Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy. FAU - Sorrentino, Rosa AU - Sorrentino R AUID- ORCID: 0000-0002-9632-2383 AD - Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy. FAU - D'Abramo, Marco AU - D'Abramo M AUID- ORCID: 0000-0001-6020-8581 AD - Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy. FAU - Fiorillo, Maria Teresa AU - Fiorillo MT AUID- ORCID: 0000-0002-6859-5851 AD - Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, 00185 Rome, Italy. LA - eng GR - 1./Sapienza University of Rome/ GR - 2./Ceschina Foundation/ PT - Journal Article DEP - 20230828 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (HLA-B Antigens) RN - 0 (Epitopes) RN - EC 3.4.11.- (ERAP1 protein, human) RN - EC 3.4.11.- (Aminopeptidases) RN - 0 (Minor Histocompatibility Antigens) RN - EC 3.4.11.- (ERAP2 protein, human) SB - IM MH - Humans MH - Haplotypes MH - *Genes, MHC Class I MH - HLA-B Antigens/genetics MH - CD8-Positive T-Lymphocytes MH - Epitopes MH - *Spondylitis, Ankylosing/genetics MH - Aminopeptidases/genetics MH - Minor Histocompatibility Antigens/genetics PMC - PMC10488187 OTO - NOTNLM OT - CD8+ T cells OT - Endoplasmic Reticulum AminoPeptidase (ERAP)1 and ERAP2 haplotypes OT - ankylosing spondylitis OT - anti-viral immunity OT - antigen processing and presentation OT - human leukocyte antigen (HLA)-B*27 OT - peptides COIS- The authors declare no conflict of interest. EDAT- 2023/09/09 11:45 MHDA- 2023/09/11 06:43 PMCR- 2023/08/28 CRDT- 2023/09/09 01:12 PHST- 2023/07/28 00:00 [received] PHST- 2023/08/22 00:00 [revised] PHST- 2023/08/25 00:00 [accepted] PHST- 2023/09/11 06:43 [medline] PHST- 2023/09/09 11:45 [pubmed] PHST- 2023/09/09 01:12 [entrez] PHST- 2023/08/28 00:00 [pmc-release] AID - ijms241713335 [pii] AID - ijms-24-13335 [pii] AID - 10.3390/ijms241713335 [doi] PST - epublish SO - Int J Mol Sci. 2023 Aug 28;24(17):13335. doi: 10.3390/ijms241713335.