CD8tissue-resident memory T cells are expanded in primary Sjögren's disease and can be therapeutically targeted by CD103 blockade.

in Annals of the rheumatic diseases by Daniele Mauro, Xiang Lin, Elena Pontarini, Pascale Wehr, Giuliana Guggino, Yuan Tang, Chong Deng, Saviana Gandolfo, Fan Xiao, Ke Rui, Enyu Huang, Jie Tian, Stefania Raimondo, Maureen Rischmueller, Jane Boroky, Sarah Downie-Doyle, Hendrik Nel, Adriana Baz-Morelli, Arthur Hsu, Eugene Maraskovsky, Adele Barr, Patrice Hemon, Loukas Chatzis, Ciro Emiliano Boschetti, Giuseppe Colella, Riccardo Alessandro, Aroldo Rizzo, Jacques-Olivier Pers, Michele Bombardieri, Ranjeny Thomas, Liwei Lu, Francesco Ciccia

TLDR

  • The study looked at cells in the salivary glands of people with primary Sjogren's syndrome (pSS) and compared them to cells in the salivary glands of people without pSS. The study found that these cells, called tissue-resident memory cells (Trm), were more common in people with pSS and were involved in inflammation and tissue damage. The study also found that blocking a specific protein on these cells, called CD103, could reduce inflammation and improve salivary flow in people with pSS.

Abstract

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). 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. 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 CD8CD103CD69cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8CD103Trm contributed to the secretion of granzyme-B and interferon-γ, CD8Trm 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 ofandamong CD3CD8SG T cells. In the SG of ESS, CD8CD69CD103Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow. CD103CD8Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.

Overview

  • The study investigates the phenotype and function of tissue-resident memory cells (Trm) in primary Sjogren's syndrome (pSS) and non-pSS sicca syndrome patients. The study examines Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB), and analyzes Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). The study also investigates Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assesses the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration. The primary objective of the study is to understand the role of CD103 in pSS and to identify Trm as a potential therapeutic target for pSS and ESS.

Comparative Analysis & Findings

  • The study found that 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 CD8CD103CD69cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8CD103Trm contributed to the secretion of granzyme-B and interferon-γ, CD8Trm 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 ofandamong CD3CD8SG T cells. In the SG of ESS, CD8CD69CD103Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow. CD103CD8Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.

Implications and Future Directions

  • The study's findings suggest that CD103 plays a crucial role in the pathogenesis of pSS and ESS, and that Trm cells are a potential therapeutic target for these diseases. The study identifies CD103CD8Trm cells as a potential therapeutic target for pSS and ESS, and suggests that intraglandular blockade of CD103 can reduce glandular damage and improve salivary flow in ESS. The study also identifies CD8CD103Trm cells as a potential therapeutic target for pSS and ESS, and suggests that scRNAseq can be used to identify potential therapeutic targets for these diseases. Future research should focus on developing targeted therapies for pSS and ESS that specifically target CD103CD8Trm cells and other Trm cells.
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