Interleukin‐7/Interferon Axis Drives T Cell and Salivary Gland Epithelial Cell Interactions in Sjögren’s Syndrome

Abstract

Objective. Primary Sjögren's syndrome (SS) is characterized by a lymphocytic infiltration of salivary glands (SGs) and the presence of an interferon (IFN) signature. SG epithelial cells (SGECs) play an active role in primary SS pathophysiology. We undertook this study to examine the interactions between SGECs and T cells in primary SS and the role of the interleukin-7 (IL-7)/IFN axis. Methods. Primary cultured SGECs from control subjects and patients with primary SS were stimulated with poly(I-C), IFNα, or IFNγ. T cells were sorted from blood and stimulated with IL-7. CD25 expression was assessed by flow cytometry. SG explants were cultured for 4 days with anti-IL-7 receptor (IL-7R) antagonist antibody (OSE-127), and transcriptomic analysis was performed using the NanoString platform. Results. Serum IL-7 level was increased in patients with primary SS compared to controls and was associated with B cell biomarkers. IL7R expression was decreased in T cells from patients with primary SS compared to controls. SGECs stimulated with poly(I-C), IFNα, or IFNγ secreted IL-7. IL-7 stimulation increased the activation of T cells, as well as IFNγ secretion. Transcriptomic analysis of SG explants showed a correlation between IL7 and IFN expression. Finally, explants cultured with anti-IL-7R antibody showed decreased IFN-stimulated gene expression. Conclusion. These results suggest the presence of an IL-7/IFNγ amplification loop involving SGECs and T cells in primary SS. IL-7 was secreted by SGECs stimulated with type I or type II IFN and, in turn, activated T cells that secrete type II IFN. An anti-IL-7R antibody decreased the IFN signature in T cells in primary SS and could be of therapeutic interest.

Epithelial–immune cell interplay in primary Sjögren syndrome salivary gland pathogenesis

“…In pSS, the function of this recep tor is thought to be impaired in the ductal cells; indeed, in SGECs from patients with Sjögren syndrome, intra cellular levels of CXCL10 are reduced compared with SGECs from healthy individuals, which is presumed to be a consequence of impaired CXCR3 functionality permitting the accumulation of these chemokines 55 . In addition to responding aberrantly to extrinsic stimuli, striated duct cells 56,57 and SGECs 52,58 from patients with Sjögren syndrome also express many cytokines and chemokines (for example, IL1, IL6, IL7, IL18, TNF, B cellactivating factor (BAFF), CXCL10, CXCL12 and CXCL13) at higher levels than those observed in healthy individuals. Thus, striated ducts and their presumed in vitro counterpart SGECs are capable of regulating the immune response (as discussed in more detail in the section on epithelial cell-lymphocyte crosstalk).…”

“…1c). A main consequence for the glan dular epithelium is that type I interferons enhance the production of pathogenic chemokines and cytokines (for example, CXCL10, IL7 and BAFF) by ductal epithelial cells, resulting in the recruitment and activation of T cells and B cells and thereby amplifying the inflammatory response 58,143,144 .…”

“…IFNγ is not only produced by bona fide T H 1 cells in the salivary gland but also by T follicular helper (T FH )like cells that express both programmed cell death protein 1 (PD1) and induci ble T cell costimulator (ICOS) and by CCR9 + T helper cells 145,146 . IFNγ exerts proinflammatory effects on SGECs (including both labial and parotid gland derived SGECs) by stimulating the production of cytokines and chemokines 58,143 . IFNγ also induces the expression of MHC class II and costimulatory mole cules on SGECs 47,147,148 .…”

“…In the ductal epithelium of patients with pSS, IFNλ2 is upregulated compared with individuals with nonSjögren syndrome sicca symptoms 151 . Similar to type I and type II inter ferons, IFNλ can promote the production of cytokines (for example, IL7, BAFF and CXCL10) by the salivary gland epithelium 58,151 . Whether type III interferons nota bly contribute to salivary gland pathology, either inde pendent or in synergy with other interferons, remains to be elucidated.…”

“…In addition to the provision of costimulatory sig nals to T cells, SGECs can produce several cytokines and chemokines, as shown for both labial and parotid glandderived SGECs. These can include chemokines that attract T cells (for example, CCL19 and CXCL10), as well as cytokines that promote local T cell proliferation and/or differentiation 56,58,143,154 . For example, SGECs can produce IL6, a pleiotropic cytokine that can promote the differentiation of T FH cells (as well as B cells) 156 .…”