Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides

Yang, Xinbo; Garner, Lee; Zvyagin, Ivan V.; Paley, Michael; Komech, Ekaterina A.; Jude, Kevin; Xiang, Zhao; Fernandes, Ricardo A.; Hassman, Lynn M.; Paley, Grace; Savvides, Christina S; Brackenridge, Simon; Quastel, Max; Chudakov, Dmitriy M; Bowness, Paul; Yokoyama, Wayne M.; McMichael, Andrew J.; Gillespie, Geraldine M.; Garcia, K Christopher

doi:10.1038/s41586-022-05501-7

Cited by 70 publications

(46 citation statements)

References 65 publications

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“…This could be useful in cancer immunotherapy by either the upregulation of existing or presentation of novel cancer neoantigens 45 which would enhance existing or generate novel immune responses against the tumor. Conversely, in the case of HLA-associated autoimmunity 46 , the downregulation of speci c selfpeptides that activate disease-associated cytotoxic T cells could have therapeutic applications 47,48 . In both cases, the therapeutic outcome could result from manipulating the presentation of a few antigenic peptides which can be achieved by inducing "surgical" shifts to the immunopeptidome of the cells.…”

Section: Discussionmentioning

confidence: 99%

Distinct modulation of cellular immunopeptidome by the allosteric regulatory site of ER aminopeptidase 1

Temponeras

Samiotaki

Koumantou

et al. 2023

Preprint

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ER aminopeptidase 1 (ERAP1) is an ER-resident aminopeptidase that excises N-terminal residues off peptides that then bind onto Major Histocompatibility Complex I molecules (MHC-I) and indirectly modulates adaptive immune responses. ERAP1 contains an allosteric regulatory site that accommodates the C-terminus of at least some peptide substrates, raising questions about its exact influence on antigen presentation and the potential of allosteric inhibition for cancer immunotherapy. We used an inhibitor that targets this regulatory site to study its effect on the immunopeptidome of a human cancer cell line. The immunopeptidomes of allosterically inhibited and ERAP1 knockout cells contain high-affinity peptides with sequence motifs consistent with the cellular HLA class I haplotypes, but were strikingly different in peptide composition. Compared to knockout cells, allosteric inhibition did not affect the length distribution of peptides and skewed the peptide repertoire both in terms of sequence motifs and HLA allele utilization, indicating significant mechanistic differences between the two ways of disrupting ERAP1 function. These findings suggest that the regulatory site of ERAP1 plays distinct roles in antigenic peptide selection, which should be taken into consideration when designing therapeutic interventions targeting the cancer immunopeptidome.

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Section: Discussionmentioning

confidence: 99%

Distinct modulation of cellular immunopeptidome by the allosteric regulatory site of ER aminopeptidase 1

Temponeras

Samiotaki

Koumantou

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…29 The identification of CD8+T cells in PsO react against melanocytes in the context of HLA-C06:02 as skin-specific target cells of the psoriatic autoimmune response, [30][31][32] while CD8+T cells from synovial and eye fluid of SpA and AU patients recognise both self and microbial peptides presented by HLA-B*27. 29 There is still no conclusive evidence that this mechanism underlies other MHC-I-opathies since mechanistic studies are technically challenging to conduct, owing to multiorgan involvement having complex tissues, which requires labour-intensive technology to screen for many epitopes. Consequently, several alternative theories for MHC-I-opathies have been proposed, one of which suggests that MHC-I protein misfolding directly leads to inflammation.…”

Section: The Inception Of the Mhc-i-opathy Familymentioning

confidence: 99%

“…143 144 Researchers recently found that tissue-infiltrating CD8+T cells shared TCRs in eye liquid as well as synovial fluid of HLA-B*27-positive patients with AS and AU. 29 These CD8+T cells specifically recognise microbial (eg, YEIH protein from reactive arthritis-triggering pathogens) and self-antigens (eg, peptides from GPER1 or PRPF3 proteins) specifically within the context of HLA-B27. According to these findings, environmental pathogens may trigger autoimmunity via CD8+T cell activation in MHC-I-opathies, thus supporting the primary hypothesis of the MHC-I-opathy pathogenesis.…”

Section: Unmet Needs In Mhc-i-opathy Pathophysiology Understanding Ev...mentioning

confidence: 99%

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EULAR study group on ‘MHC-I-opathy’: identifying disease-overarching mechanisms across disciplines and borders

et al. 2023

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The ‘MHC-I (major histocompatibility complex class I)-opathy’ concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet’s disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

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“…However, more therapeutic precision is still required to target tumors accurately. Moreover, multiplexed precision genome editing with pros and cons has become a highly flexible and modular toolkit for specifically addressing the challenges of precision interventions ( 35 – 37 ). Towards better functionality, genome editing tools like CRISPR/Cas9 and TALENs have made it possible to create additional genetic modifications in immune cells ( 36 , 38 , 39 ).…”

mentioning

confidence: 99%

Editorial: Complexity of tumor microenvironment: A major culprit in cancer development, volume II

et al. 2023

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Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides

Cited by 70 publications

References 65 publications

Distinct modulation of cellular immunopeptidome by the allosteric regulatory site of ER aminopeptidase 1

Distinct modulation of cellular immunopeptidome by the allosteric regulatory site of ER aminopeptidase 1

EULAR study group on ‘MHC-I-opathy’: identifying disease-overarching mechanisms across disciplines and borders

Editorial: Complexity of tumor microenvironment: A major culprit in cancer development, volume II

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