NK cell recruitment in salivary glands provides early viral control but is dispensable for tertiary lymphoid structure formation

Pontarini, Elena; Lucchesi, Davide; Fossati-Jimack, Liliane; Coleby, Rachel; Tentorio, Paolo; Croia, Cristina; Bombardieri, Michèle; Mavilio, Domenico

doi:10.1002/jlb.5a1117-462rr

Cited by 8 publications

(9 citation statements)

References 41 publications

(103 reference statements)

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“…To investigate the control of SG inflammation by IL‐27, we utilized a well‐established model of inducible sialadenitis, characterized by an early activation of the resident stroma and innate immune cells, followed by accumulation of T cells and B cells, and the formation of ELS with functional GCs (Supplementary Figure 3A, http://onlinelibrary.wiley.com/doi/10.1002/art.41289/abstract).…”

Section: Resultsmentioning

confidence: 99%

Impaired Interleukin‐27–Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome

Lucchesi

Coleby

Pontarini

et al. 2020

Arthritis & Rheumatology

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Objective Ectopic lymphoid structures (ELS) develop at sites of infection, autoimmunity, and cancer. In patients with Sjögren's syndrome (SS), ELS support autoreactive B cell activation and lymphomagenesis. Interleukin‐27 (IL‐27) is a key regulator of adaptive immunity and limits Th17 cell–driven pathology. We undertook this study to elucidate the role of IL‐27 in ELS formation and function in autoimmunity using a murine model of sialadenitis and in patients with SS. Methods ELS formation was induced in wild‐type and Il27ra−/− mice via salivary gland (SG) cannulation of a replication‐deficient adenovirus in the presence or absence of IL‐17A neutralization. In SG biopsy samples, IL‐27–producing cells were identified by multicolor immunofluorescence microscopy. Lesional and circulating IL‐27 levels were determined by gene expression and enzyme‐linked immunosorbent assay. The in vitro effect of IL‐27 on T cells was assessed using fluorescence‐activated cell sorting and cytokine release. Results In experimental sialadenitis, Il27ra−/− mice had larger and more hyperactive ELS (focus score; P < 0.001), increased autoimmunity, and an expanded Th17 response (P < 0.001), compared to wild‐type mice. IL‐17 blockade in Il27ra−/− mice suppressed the aberrant ELS response (B and T cell reduction against control; P < 0.01). SS patients displayed increased circulating IL‐27 levels (P < 0.01), and in SG biopsy samples, IL‐27 was expressed by DC‐LAMP+ dendritic cells in association with CD3+ T cells. Remarkably, in SS T cells (but not in T cells from patients with rheumatoid arthritis or healthy controls), IL‐27–mediated suppression of IL‐17 secretion was severely impaired and associated with an aberrant interferon‐γ release upon IL‐27 stimulation. Conclusion Our data indicate that the physiologic ability of IL‐27 to limit the magnitude and function of ELS through control of Th17 cell expansion is severely impaired in SS patients, highlighting a defective immunoregulatory checkpoint in this condition.

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Section: Resultsmentioning

confidence: 99%

Impaired Interleukin‐27–Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome

Lucchesi

Coleby

Pontarini

et al. 2020

Arthritis & Rheumatology

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“…Here, CD4 + T cells are high producers of this cytokine throughout the time course. Importantly and shown previously, NK cells are also key producers of granzyme-B and IFN-γ within the SG at early time points after viral infection (between 3 and 10 dpc) (27). We therefore hypothesise that while NK cells greatly decrease in number by 10 dpc ( 27), T cells expand and take over the production of these effector molecules.…”

Section: Functional Phenotype Of Infiltrating T Cellsmentioning

confidence: 53%

“…Finally, inducible models utilise Ro, M3R or other antigens to immunise mice leading to autoantibody production and impaired SG function (23,24). Recently, we demonstrated that a virusinduced murine model of SG inflammation and ELS formation developed in our laboratory (25), can be used to study the role of key players in ELN (25)(26)(27)(28). This model recapitulates some of the characteristics of SS, including periductal lymphoid aggregates, ELS and breach of self-tolerance within 19 days of viral infection (25).…”

Section: Introductionmentioning

confidence: 95%

Stepwise changes in the murine salivary gland immune response during virally-induced ectopic lymphoid structure formation

Coleby

Lucchesi

Pontarini

et al. 2021

Clinical and Experimental Rheumatology

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Objective. Sjögren's syndrome (SS) is a chronic autoimmune disease characterised by lymphocytic infiltration into the salivary glands (SG) and, in a subset of patients, formation of ectopic lymphoid structures (ELS) in the glands. However, the mechanisms of how ELS form ectopically are not fully elucidated. Here we used a viral inducible murine model of ELS formation in the SG to elucidate the key immunological steps regulating the formation of ELS in the SG. Methods. We have utilised an inducible murine model of sialadenitis whereby retrograde cannulation of the submandibular SG with a replication-deficient adenovirus 5 leads to the formation of ELS. Flow cytometry, immunofluorescence and gene expression was performed on the SGs at regular time points after cannulation to follow the organisation of ELS. Results. Innate immune cells (neutrophils, eosinophils and monocytes) rapidly infiltrated the SG by 3 days post cannulation (dpc) whereby monocytes started to differentiate into resident macrophages. Myeloid dendritic cells accumulated inside leukocytic aggregates whereas macrophages were excluded from the developing ELS. Meanwhile, CD11b+ cells upregulated Il18, Cxcl13, Ltb, April and other lymphoid genes stimulating the influx of T cells by 12 days and B cells shortly after. Infiltration of T-follicular helper (Tfh) cells correlated with an increase in GL7+germinal centre B cells, which peaked at 19 dpc. Conclusions. Immune cell infiltration in virally-infected murine SG follows a highly reproducible step-wise process whereby early innate immune cells reshape the SG myeloid compartment leading to upregulation of genes involved in the ectopic lymphoid neogenesis process. This in turns leads to T and B cell recruitment, differentia-tion and activation, culminating in the organisation of ELS and localised germinal centres responses.

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“…Since both bacterial and viral agents have been implicated in the pathogenesis of periodontal disease [44][45][46][47], it is likely that suboptimal induction of IFN-γ will have profound effects on the clearance of both types of organism and the resolution of inflammation [48][49][50]. Therefore, the increase in the numbers and activation of NK cells in periodontal infection may have a direct relationship to the increase in colonization with the viral and bacterial infections since NK cells are the primary effectors that mediate lysis of virally infected cells.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Functional Alterations of Immune Effectors in Periodontitis; A Multifactorial and Complex Oral Disease

Kaur

Vaziri

Jewett

2021

JCM

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Survival and function of immune subsets in the oral blood, peripheral blood and gingival tissues of patients with periodontal disease and healthy controls were assessed. NK and CD8 + T cells within the oral blood mononuclear cells (OBMCs) expressed significantly higher levels of CD69 in patients with periodontal disease compared to those from healthy controls. Similarly, TNF-α release was higher from oral blood of patients with periodontal disease when compared to healthy controls. Increased activation induced cell death of peripheral blood mononuclear cells (PBMCs) but not OBMCs from patients with periodontal disease was observed when compared to those from healthy individuals. Unlike those from healthy individuals, OBMC-derived supernatants from periodontitis patients exhibited decreased ability to induce secretion of IFN-γ by allogeneic healthy PBMCs treated with IL-2, while they triggered significant levels of TNF-α, IL-1β and IL-6 by untreated PBMCs. Interaction of PBMCs, or NK cells with intact or NFκB knock down oral epithelial cells in the presence of a periodontal pathogen, F. nucleatum, significantly induced a number of pro-inflammatory cytokines including IFN-γ. These studies indicated that the relative numbers of immune subsets obtained from peripheral blood may not represent the composition of the immune cells in the oral environment, and that orally-derived immune effectors may differ in survival and function from those of peripheral blood.

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NK cell recruitment in salivary glands provides early viral control but is dispensable for tertiary lymphoid structure formation

Cited by 8 publications

References 41 publications

Impaired Interleukin‐27–Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome

Impaired Interleukin‐27–Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome

Stepwise changes in the murine salivary gland immune response during virally-induced ectopic lymphoid structure formation

Phenotypic and Functional Alterations of Immune Effectors in Periodontitis; A Multifactorial and Complex Oral Disease

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