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Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

ABSTRACT: Sjogren’s Disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, and extra glandular manifestations. The etiology and pathophysiology of SjD are incompletely understood. Regulatory T (Treg) cells are critical for immunological tolerance and although Treg abnormalities have been implicated in the pathogenesis of several autoimmune diseases, their role in SjD remains ambiguous. We here show that Stim1fl/flStim2fl/flFoxp3-Cre (Stim1/Stim2 Foxp3cre) mice develop a SjD-like phenotype, including severe sialadenitis with hyposalivation, lacrimal gland (LG) inflammation with dry eye and corneal damage, increased anti-Ro and anti-La autoantibody levels and interstitial lung disease. At the cellular level, salivary gland inflammation in Stim1/2Foxp3 mice is characterized by infiltration with CD4+ and CD8+ T cells, which is dominated by a T helper (Th) 1 and Th2 immune response. The changes in gene expression in SGs of mice correlate strongly with transcriptional and epigenetic dysregulation found in SjD patients. Our findings in Stim1/Stim2 Foxp3cre mice provide new evidence for a critical role of Treg cells and IFNγ producing Th1 cells in mediating SjD progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE253188 | GEO | 2024/11/04

REPOSITORIES: GEO

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Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren’s Syndrome

Project description:Sjogren’s Disease (SjD) is an autoimmune disorder characterized by progressive inflammation and destruction of both salivary and lacrimal gland leading to dysfunction, as well as extra glandular manifestations. The etiology and pathophysiology of SjD are incompletely understood. Regulatory T (Treg) cells are critical for immunological tolerance. Although Treg abnormalities have been implicated in the pathogenesis of several autoimmune diseases, their role in SjD remains ambiguous. We had previously shown that the function and development of Treg cells depend on store-operated Ca2+ entry (SOCE), which is mediated by ORAI1 Ca2+ channels and stromal interaction molecules (STIM) 1 and 2 following T cell receptor (TCR) stimulation. The ablation of SOCE in Treg cells causes SjD-like disease with increased Th1 and interferon gene expression signatures in the inflamed salivary glands of mice. Here we show enhanced Th1 gene expression signatures and type I and II interferon responses in the peripheral blood mononuclear cells (PBMCs) of human patients with SjD compared to non-SjD controls. We also identified attenuated gene expression in memory Treg cells of patients with SjD. These data from mice and human patients provide new evidence for a critical role of Treg cells and IFNγ producing Th1 cells in the pathogenesis of SjD.

2024-11-04 | GSE253568 | GEO

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Project description:T follicular helper (TFH) cells promote affinity maturation of B cells in germinal centers (GCs), whereas T follicular regulatory (TFR) cells limit GC reaction. Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels mediated by STIM and ORAI proteins is a fundamental signaling pathway in T lymphocytes. Here we show that SOCE is required for the differentiation and function of both TFH and TFR cells. Conditional deletion of Stim1 and Stim2 genes in T cells or Treg cells results in spontaneous autoantibody production and humoral autoimmunity. Conversely, antibody-mediated immune responses following viral infection critically depend on SOCE in TFH cells. Mechanistically, STIM1 and STIM2 control early TFR and TFH cell differentiation through NFAT-mediated IRF4, BATF and Bcl-6 expression. SOCE plays a dual role in GC response by controlling TFH and TFR cell function, thus enabling protective B cell responses and preventing humoral autoimmunity. RNAseq analyses of WT and Stim1Stim2 DKO follicular T cells and non-follicular T cells; 4-6 mice per cohort in duplicates. Mice were infected for 10 days with LCMV.

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Aquaporin gene therapy corrects Sjogren's syndrome phenotype in mice

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2014-08-12 | E-GEOD-60318 | biostudies-arrayexpress

Transcriptome data of Foxp3-Cre, Rbx1&Sag-deficient Treg cells from mice

Project description:Neddylation is necessary for activation of Cullin-RING Ligases (CRLs) which degrade various immune regulatory proteins. Our recent study showed that while depletion of neddylation E2-E3 pair Ube2f-Sag in regulatory T cells (Treg cells) had no obvious phenotype, the same depletion of either Ube2m or Rbx1 caused inflammation disorders with different severity. Whether these E2s or E3s compensate each other in functional regulations of Treg cells is, however, previously unknown. In this report, we generated Foxp3Cre;Ube2mfl/fl;Ube2ffl/fl or Foxp3Cre;Rbx1fl/fl;Sagfl/fl double null mice by simultaneously deletion of both neddylation E2s or E3s in Treg cells, respectively. Remarkably, Ube2m&Ube2f double null mice developed much severe autoimmune phenotypes than Ube2m-null mice, indicating Ube2m significantly compensates Ube2f in Treg cells. The minor worsen autoimmune phenotypes seen at very early stage in Rbx1&Sag double null than Rbx1-null mice, is likely due to already severe phenotypes of the later, indicating a minor compensation of Rbx1 for Sag. The RNA profiling-based analyses revealed that up- and down-regulations of few signaling pathways in Treg cells are associated with the severity of autoimmune phenotypes. Finally, severer inflammation phenotypes seen in mice with double E3-null than with double E2-null Treg cells indicate a neddylation-independent mechanism of two E3s, also known to serve as the RING component of CRLs in regulation of Treg cell fitness.

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Transcriptome data of Foxp3-Cre, Ube2m&Ube2f-deficient Treg cells from mice

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STIM1 and STIM2 mediate cancer-induced inflammation in T cell acute lymphoblastic leukemia

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of T cell progenitors that in most patients is associated with activating mutations in the NOTCH1 pathway. Recent reports have indicated a link between Ca2+ homeostasis in the endoplasmic reticulum (ER), the regulation of NOTCH1 signaling and T-ALL. Here we investigated the role of store-operated Ca2+ entry (SOCE) in T-ALL. SOCE is a Ca2+ influx pathway that is mediated by the plasma membrane Ca2+ channel ORAI1 and its activators STIM1 and STIM2. Deletion of STIM1 and STIM2 in leukemic cells abolished SOCE and significantly prolonged the survival of mice in a NOTCH1-driven model of T-ALL. The survival advantage was unrelated to leukemia development and leukemic cell burden, but was associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with wildtype T-ALL showed a severe necroinflammatory response in their bone marrow, which was absent in mice with Stim1/2-/- leukemia. Several signaling pathways previously linked to cancer-induced inflammation were downregulated in Stim1/2-/- leukemic cells, likely accounting for less aggressive leukemia progression and prolonged survival of mice. Our study shows that T-ALL is associated with inflammation of leukemia-infiltrated organs and that SOCE controls the proinflammatory effects of leukemic T lymphoblasts.

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Project description:Background: The study of human lacrimal gland biology and development is limited. Lacrimal gland tissue is damaged or poorly functional in a number of disease states including dry eye disease. Development of cell based therapies for lacrimal gland diseases requires a better understanding of the gene expression and signaling pathways in lacrimal gland. Differential gene expression analysis between lacrimal gland and other embryologically similar tissues may be helpful in furthering our understanding of lacrimal gland development. Methods: We performed global gene expression analysis of human lacrimal gland tissue using Affymetrix ® gene expression arrays. Primary data from our laboratory was compared with datasets available in the NLM GEO database for other surface ectodermal tissues including salivary gland, skin, conjunctiva and corneal epithelium. Results: The analysis revealed statistically significant difference in the gene expression of lacrimal gland tissue compared to other ectodermal tissues. The lacrimal gland specific, cell surface secretory protein encoding genes and critical signaling pathways which distinguish lacrimal gland from other ectodermal tissues are described. Conclusions: Differential gene expression in human lacrimal gland compared with other ectodermal tissue types revealed interesting patterns which may serve as the basis for future studies in directed differentiation among other areas.

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