Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sjögren's syndrome
Introduction
Primary Sjögren's syndrome (pSS), which is the most common systemic autoimmune disease after rheumatoid arthritis, presents as a disabling sicca syndrome associated with asthenia and pain. One third of the patients develop systemic manifestations [1]. The pathogenesis of pSS involves both genetic and environmental factors, which trigger the activation of innate and adaptive immunity [2], [3].
Primary Sjögren's syndrome is an autoimmune epithelitis in which salivary gland epithelial cells (SGECs) play a crucial pathogenic role [4]. This role is particularly well illustrated in the NOD/scid mice model, in which features of epithelial cell activation can be observed in the absence of T, B and NK cells [5]. Likewise, poly I:C stimulated NZB/NZWF1 mice also develop dryness before the occurrence of salivary lymphocytic infiltrates [6]. In patients with pSS, the capacity of SGECs to secrete cytokines (IL-1, IL-6 and B-cell activating factor of the TNF family (BAFF)) and chemokines, as well as to present auto-antigens, was previously reported [7], [8], [9]. SGECs also express various molecules implicated in immune response, including TLRs [10], MHC I and MHC II, CD80, CD86 and CD40, Fas and FasL [11], [12]. SGECs also undergo major epigenetic changes that could play a role in the pathogenesis of the disease [13]. However, data regarding the role of SGECs in T cell differentiation and activation are limited and a precise description, at the molecular level, of their contribution to the pathogenesis of Sjögren's syndrome is still lacking. Presence of different T cell subsets was evidenced in pSS, in peripheral blood and in salivary glands, including Th1, Th2, Th17, and regulatory T cells [3], [14], [15], [16]. Follicular helper T cells (Tfh) represent the main T cell subset capable to activate B cells in lymphoid organs. Tfh are notably crucial for the formation and maintenance of germinal center [17], [18]. Tfh might contribute to B cell activation, a hallmark of this disease frequently associated with polyclonal hypergammaglobulinemia and autoantibody secretion. These properties notably result from Tfh-B lymphocytes cell surface interactions through expression of CXC chemokine receptor 5 (CXCR5), inducible T cell co-stimulator (ICOS) and secretion of IL-21. IL-21, which is mainly secreted by Tfh, is a key cytokine involved in B cell activation [19]. An increase in blood Tfh-like cells in pSS was reported, as well as elevated IL-21 and IL-21 receptor expression in salivary glands [20], [21], [22], [23], [24], [25] and the pathogenic role of Tfh and IL-21, a potent immunostimulatory cytokine, has been suggested in other autoimmune diseases (AIDs), like systemic lupus erythematosus or rheumatoid arthritis [26], [27], [28], [29]. Furthermore, association between gene polymorphisms of Il-21 and Grave's disease, rheumatoid arthritis, lupus, celiac disease and type I diabetes was reported [30], [31], [32], [33], [34] as well as between a gene polymorphism of the Il-21 receptor gene and lupus [35].
In the present study, we investigated the capability of SGECs to induce Tfh differentiation and IL-21 secretion. Our work pointed to a prominent role of SGECs in the promotion of follicular helper T cells differentiation and IL-21 secretion through IL-6 and ICOSL expression. We also demonstrated an increase in serum IL-21 with systemic disease activity. We last analyzed the potential association between 3 single-nucleotide polymorphisms of IL-21 and IL-21 receptor genes and pSS.
Section snippets
Salivary gland epithelial cells
Primary cultures of SGECs from 8 patients with pSS according to European American Consensus Group criteria and 6 controls (sicca syndrome without any feature of autoimmunity: no autoantibody, no salivary gland lymphocytic infiltrate) were established from minor salivary gland biopsies as previously described [36]. These patients were addressed to the National Reference Center for AutoImmune Diseases of Strasbourg for dry symptoms. These patients were not part of the Assessment of Systemic Signs
Salivary gland epithelial cells induce follicular helper T cell differentiation
Given the pivotal role of salivary gland epithelial cells in the pathogenesis of pSS [1], [2], [3], we investigated whether these cells could induce the differentiation of naïve CD4+ T cells into follicular helper T cells. SGECs were isolated from minor salivary gland biopsies. To exclude cell dedifferentiation during primary culture, epithelial cells were characterized by immunohistochemistry. All tested samples were positive for cytokeratin 7, cytokeratin 19 and vimentin which confirmed their
Discussion
This study demonstrates the capacity of salivary gland epithelial cells to induce the differentiation of the main T cell subset that secretes IL-21, follicular helper T cells. It also provides important insights at the molecular level regarding the mechanisms by which this essential immune event occurs and participates in the pathogenesis of Sjögren's syndrome. The presence of follicular helper T cells and local IL-21 secretion were recently evidenced in salivary glands of patients with pSS,
Funding
Institutional funding from INSERM and Université de Strasbourg are acknowledged. Ya-Zhuo Gong's work was supported by grants from the Société Française de Rhumatologie (SFR). The study was supported by a grant from the Association Française Gougerot-Sjögren. The ASSESS cohort received a grant from the SFR.
Acknowledgments
We thank patients with pSS included in the ASSESS cohort; Direction de la Recherche Clinique (DRC) de l’Assistance Publique des Hôpitaux de Paris and Myriem Carrier; Djilali Batouche, Karine Inamo, Stanie Gaete, Laina Ndiaye, Helene Agostini and Laurent Becquemont (Unité de Recherche Clinique Paris Sud); Mickael Randrianandrasana, Isabelle Pane, Adeline Abbe, Gabriel Baron (Epidémiologie et Santé Publique, Hotel Dieu); Centre de Ressources Biologiques de l’Hôpital Bichat; the French Society of
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2021, CytokineCitation Excerpt :Th17-, Tfh- and T peripheral helper (Tph)-associated effector functions, including expression of IL-17, IL-22, IL-21 and ICOS are associated with the development of ELS in various models of autoimmunity, inflammation and infection that affect the lung (iBALT), salivary glands, retina, synovium and aorta [3,44,68]. In Sjögren's syndrome, salivary gland epithelial cells produce IL-6 and drive Tfh cell differentiation [126]. Notably, the expansion of IL-21-producing Tfh and Tph cells in salivary glands was recently shown to identify Sjögren's syndrome patients with ELS and parotid B cell MALT lymphomas [44].
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Ghada Alsaleh and Jacques-Eric Gottenberg contributed equally to this work.