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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., Competing Interests: 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., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)