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  • CD8+ tissue-resident memory T cells are expanded in primary Sjögren’s disease and can be therapeutically targeted by CD103 blockade

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Sjögren’s syndrome
CD8+ tissue-resident memory T cells are expanded in primary Sjögren’s disease and can be therapeutically targeted by CD103 blockade
  1. Daniele Mauro1,
  2. Xiang Lin2,
  3. Elena Pontarini3,
  4. Pascale Wehr4,
  5. Giuliana Guggino5,
  6. Yuan Tang6,
  7. Chong Deng2,
  8. Saviana Gandolfo7,
  9. Fan Xiao2,
  10. Ke Rui8,
  11. Enyu Huang2,
  12. Jie Tian8,
  13. Stefania Raimondo9,
  14. Maureen Rischmueller10,
  15. Jane Boroky10,
  16. Sarah Downie-Doyle10,
  17. Hendrik Nel4,
  18. Adriana Baz-Morelli11,
  19. Arthur Hsu11,
  20. Eugene Maraskovsky11,
  21. Adele Barr11,
  22. Patrice Hemon12,
  23. Loukas Chatzis13,
  24. Ciro Emiliano Boschetti14,
  25. Giuseppe Colella14,
  26. Riccardo Alessandro9,
  27. Aroldo Rizzo15,
  28. Jacques-Olivier Pers16,17,
  29. Michele Bombardieri3,
  30. Ranjeny Thomas18,
  31. Liwei Lu6,
  32. Francesco Ciccia1
  1. 1 Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
  2. 2 Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, Hong Kong
  3. 3 Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, UK
  4. 4 Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, Queensland, Australia
  5. 5 PROMISE -Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology section - “P. Giaccone”, University of Palermo, Palermo, Italy
  6. 6 Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong
  7. 7 Rheumatology Unit, Naples, Ospedale San Giovanni Bosco, Napoli, Italy
  8. 8 Department of Laboratory Medicine, Affiliated Hospital and Institute of Medical Immunology, Jiangsu University, Zhenjiang, Jiangsu, China
  9. 9 Dipartimento di Biomedicina, Neuroscienze e Diagnostica Avanzata (Bi.N.D), University of Palermo, Palermo, Italy
  10. 10 The Queen Elizabeth Hospital and Medical School, University of Adelaide, South Australia, South Australia, Australia
  11. 11 Bio21 Institute, CSL Limited, Parkville, Victoria, Australia
  12. 12 Université de Brest, Centre Hospitalier Universitaire de Brest, INSERM, Paris, France
  13. 13 National and Kapodistrian University of Athens Faculty of Medicine, Athens, Greece
  14. 14 Dipartimento Multidisciplinare di Specialità Medico-Chirurgiche e Odontoiatriche, University of Campania Luigi Vanvitelli, Caserta, Italy
  15. 15 Azienda Ospedaliera Villa Sofia-Cervello, Palermo, Italy
  16. 16 Hospitalier Universitaire de Brest, INSERM, Paris, France
  17. 17 FOC Iroise, Brest, France
  18. 18 University of Queensland Diamantina Institute, Brisbane, Queensland, Australia
  1. Correspondence to Professor Francesco Ciccia; francesco.ciccia{at}unicampania.it

Abstract

Objective Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren’s syndrome (pSS).

Methods In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration.

Results Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8+CD103+CD69+ cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8+ CD103+ Trm contributed to the secretion of granzyme-B and interferon-γ, CD8+ Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of CD69, ITGAE, GZMB, GZMK and HLA-DRB1 among CD3+CD8+ SG T cells. In the SG of ESS, CD8+CD69+CD103+ Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow.

Conclusions CD103+CD8+Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.

  • Autoimmunity
  • Chemokines
  • Sjogren's Syndrome
  • T-Lymphocyte subsets
  • Therapeutics

Data availability statement

Data are available in a public, open access repository. The single-cell data have been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE252724 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE252724). RNA-seq data have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-10517. The single-cell data have been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE252724 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE252724).

https://doi.org/10.1136/ard-2023-225069

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    Data availability statement

    Data are available in a public, open access repository. The single-cell data have been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE252724 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE252724). RNA-seq data have been deposited in the ArrayExpress database at EMBL-EBI (www.ebi.ac.uk/arrayexpress) under accession number E-MTAB-10517. The single-cell data have been deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE252724 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE252724).

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    Footnotes

    • LL and FC are joint senior authors.

    • Handling editor Josef S Smolen

    • X @dranielmar, @Elena Pontarini

    • Contributors Conceptualisation and design: FC and DM. Experiments and data collection: DM, XL, EP, PW, GG, YT, CD, FX, KR, EH, JT, SR, MR, JB, SD-D, HN, AB-M, AB, AH, EM, LC, CEB, GC, RA, AR and PH. Data analysis and interpretation: DM, XL, EP, PW, J-OP, RT and LL. Writing–original draft: DM, FC and RT. Critical revisions and editing: DM, MB, J-OP, FC, RT, SG and EP. Visualisation and figures creation: DM, XL, EP, PW and JT. Supervision and guidance: FC, RT and LL. Project administration and coordination: FC. Funding acquisition and resources: FC, LL, RT and MB. In preparing our manuscript, AI technology was employed solely for the purpose of identifying typographical errors and misspellings. No artificial intelligence tools were used for generating intellectual content or conducting data analysis. Guarantor: FC.

    • Funding This work was supported by the National Natural Science Foundation of China (81771761 and 91842304), the General Research Fund from Hong Kong Research Grants Council (17149716 and 17113319), Hong Kong Croucher Foundation (260960116) and CSL.

    • Competing interests RT has filed provisional patents surrounding technology for targeting DCs for antigen-specific tolerance (US patent 9017697 B2: 2006, PCT/AU2013/000303) and is developing immunotherapy to target DCs to suppress autoimmune disease in collaboration with CSL. AB-M and AB are employees of CSL. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.