Background/Purpose: Sjögren’s disease (SjD) is a chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, particularly the salivary glands. These focal lymphocytic infiltrates are typically dominated by heterogeneous populations of T cells, including CD4+ and CD8+ T cells, as well as unconventional double-negative (DN) T cells that lack CD4 and CD8. DN T cells have been associated with higher inflammatory activity,^1-2 but whether they participate directly in glandular dysfunction is unknown. Identifying activated in situ T cells from this heterogeneous cell population is crucial for elucidating SjD mechanisms and identifying therapeutic targets. In this study, we investigate the activation and function of salivary gland T cells in a co-culture model with salivary gland organoids.

Methods: Cryopreserved salivary gland biopsies from SjD patients were thawed and cultured to develop human salivary organoids. Salivary organoids and salivary T cells were cultured as distinct populations and also in co-culture in serum-free, defined conditions containing growth factors. T cell phenotypes were analyzed using flow cytometry and immunofluorescence, focusing on activation state, degranulation, cytokine production, and cytotoxicity.

Results: Whereas long-term T cell culture preserved distinct CD4, CD8, and DN T cell populations, co-culture with salivary organoids led to a relative increase in the DN T cell population. Some DN T cells expressed activation-induced markers CD25 and ICOS, suggesting antigen-specific activation. These cells showed significant cytokine production, including IFNγ and IL-17A, with some cells being polyfunctional, producing both IFNγ and IL-17A. Organoid-stimulated T cells also expressed CD107a, a marker of degranulation, and produced granzyme B, indicating cytotoxic activity.

Conclusion: This novel model using human salivary organoid and T cell co-culture from patient-derived samples in  defined conditions provides a valuable tool for studying factors that drive tissue T cell activation in SjD. Our findings highlight the significant role of salivary gland T cells, including the unconventional DN T cell population, in glandular damage and offer new insights into the cellular mechanisms driving SjD.

References 

1.     Alunno, Alessia, et al. “IL-17-producing CD4− CD8− T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjögren’s syndrome.” Annals of the rheumatic diseases 72.2 (2013): 286-292
2.     Alunno, Alessia, et al. “CD4− CD8− T-cells in primary Sjögren’s syndrome: association with the extent of glandular involvement.” Journal of autoimmunity 51 (2014): 38-43.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/activation-of-tissue-resident-t-cells-in-sjogrens-disease-with-human-salivary-organoids/