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IL-10 Deficiency Reveals a Role for TLR2-Dependent Bystander Activation of T Cells in Lyme Arthritis.

ABSTRACT: T cells predominate the immune responses in the synovial fluid of patients with persistent Lyme arthritis; however, their role in Lyme disease remains poorly defined. Using a murine model of persistent Lyme arthritis, we observed that bystander activation of CD4+ and CD8+ T cells leads to arthritis-promoting IFN-?, similar to the inflammatory environment seen in the synovial tissue of patients with posttreatment Lyme disease. TCR transgenic mice containing monoclonal specificity toward non-Borrelia epitopes confirmed that bystander T cell activation was responsible for disease development. The microbial pattern recognition receptor TLR2 was upregulated on T cells following infection, implicating it as marker of bystander T cell activation. In fact, T cell-intrinsic expression of TLR2 contributed to IFN-? production and arthritis, providing a mechanism for microbial-induced bystander T cell activation during infection. The IL-10-deficient mouse reveals a novel TLR2-intrinsic role for T cells in Lyme arthritis, with potentially broad application to immune pathogenesis.

SUBMITTER: Whiteside SK

PROVIDER: S-EPMC5809275 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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IL-10 Deficiency Reveals a Role for TLR2-Dependent Bystander Activation of T Cells in Lyme Arthritis.

Whiteside Sarah K SK Snook Jeremy P JP Ma Ying Y Sonderegger F Lynn FL Fisher Colleen C Petersen Charisse C Zachary James F JF Round June L JL Williams Matthew A MA Weis Janis J JJ

Journal of immunology (Baltimore, Md. : 1950) 20180112 4

T cells predominate the immune responses in the synovial fluid of patients with persistent Lyme arthritis; however, their role in Lyme disease remains poorly defined. Using a murine model of persistent Lyme arthritis, we observed that bystander activation of CD4<sup>+</sup> and CD8<sup>+</sup> T cells leads to arthritis-promoting IFN-γ, similar to the inflammatory environment seen in the synovial tissue of patients with posttreatment Lyme disease. TCR transgenic mice containing monoclonal specif ...[more]

PMID: 29330323

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Project description:Rheumatoid arthritis (RA) is a chronic destructive autoimmune disease characterised by periods of flare and remission. Today's treatment is based on continuous immunosuppression irrespective of the patient's inflammatory status. When the disease is in remission the therapy is withdrawn but withdrawal attempts often results in inflammatory flares, and re-start of the therapy is commenced when the inflammation again is prominent which leads both to suffering and increased risk of tissue destruction. An attractive alternative treatment would provide a disease-regulated therapy that offers increased anti-inflammatory effect during flares and is inactive during periods of remission. To explore this concept we expressed the immunoregulatory cytokine interleukin (IL)-10 gene under the control of an inflammation dependent promoter in a mouse model of RA - collagen type II (CII) induced arthritis (CIA). Haematopoetic stem cells (HSCs) were transduced with lentiviral particles encoding the IL-10 gene (LNT-IL-10), or a green fluorescence protein (GFP) as control gene (LNT-GFP), driven by the inflammation-dependent IL-1/IL-6 promoter. Twelve weeks after transplantation of transduced HSCs into DBA/1 mice, CIA was induced. We found that LNT-IL-10 mice developed a reduced severity of arthritis compared to controls. The LNT-IL-10 mice exhibited both increased mRNA expression levels of IL-10 as well as increased amount of IL-10 produced by B cells and non-B APCs locally in the lymph nodes compared to controls. These findings were accompanied by increased mRNA expression of the IL-10 induced suppressor of cytokine signalling 1 (SOCS1) in lymph nodes and a decrease in the serum protein levels of IL-6. We also found a decrease in both frequency and number of B cells and serum levels of anti-CII antibodies. Thus, inflammation-dependent IL-10 therapy suppresses experimental autoimmune arthritis and is a promising candidate in the development of novel treatments for RA.

Project description:BackgroundInterleukin-17 (IL-17) acts as a key regulator in central nervous system (CNS) inflammation. ?? T cells are an important innate source of IL-17. Both IL-17+ ?? T cells and microglia, the major resident immune cells of the brain, are involved in various CNS disorders such as multiple sclerosis and stroke. Also, activation of Toll-like receptor (TLR) signaling pathways contributes to CNS damage. However, the mechanisms underlying the regulation and interaction of these cellular and molecular components remain unclear.ObjectiveIn this study, we investigated the crosstalk between ?? T cells and microglia activated by TLRs in the context of neuronal damage. To this end, co-cultures of IL-17+ ?? T cells, neurons, and microglia were analyzed by immunocytochemistry, flow cytometry, ELISA and multiplex immunoassays.ResultsWe report here that IL-17+ ?? T cells but not naïve ?? T cells induce a dose- and time-dependent decrease of neuronal viability in vitro. While direct stimulation of ?? T cells with various TLR ligands did not result in up-regulation of CD69, CD25, or in IL-17 secretion, supernatants of microglia stimulated by ligands specific for TLR2, TLR4, TLR7, or TLR9 induced activation of ?? T cells through IL-1? and IL-23, as indicated by up-regulation of CD69 and CD25 and by secretion of vast amounts of IL-17. This effect was dependent on the TLR adaptor myeloid differentiation primary response gene 88 (MyD88) expressed by both ?? T cells and microglia, but did not require the expression of TLRs by ?? T cells. Similarly to cytokine-primed IL-17+ ?? T cells, IL-17+ ?? T cells induced by supernatants derived from TLR-activated microglia also caused neurotoxicity in vitro. While these neurotoxic effects required stimulation of TLR2, TLR4, or TLR9 in microglia, neuronal injury mediated by bone marrow-derived macrophages did not require TLR signaling. Neurotoxicity mediated by IL-17+ ?? T cells required a direct cell-cell contact between T cells and neurons.ConclusionTaken together, these results point to a crucial role for microglia activated through TLRs in polarization of ?? T cells towards neurotoxic IL-17+ ?? T cells.

Project description:Bacterial infections remain a significant cause of adverse pregnancy outcomes. Ascending infection of group B streptococcus (GBS) or Streptococcus agalactiae from the lower genital tract to the amniotic cavity leads to fetal injury, preterm births, or stillbirths. Factors increasing the invasive potential of bacteria at the maternal-fetal interface are poorly understood. Previous studies have indicated that the GBS hyaluronidase (HylB) can enhance systemic infection by breaking down host hyaluronan into disaccharides that dampen protective TLR2 and TLR4 signaling. Here, we examined the importance of hyaluronan receptors such as TLR2, TLR4, and CD44 in defense against GBS infections during pregnancy. While HylB promoted ascending GBS infection in wild-type (WT) and CD44-deficient mice, surprisingly, mice lacking both TLR2 and TLR4 (TLR2/4) were able to curtail these infections. Interleukin-10 (IL-10) and IL-10-expressing macrophages were significantly increased in the uterine tissues of WT mice during infection with HylB-proficient GBS compared with those of TLR2/4-deficient mice, and this likely promotes immune suppression and GBS dissemination. Consistent with these observations, pregnant IL-10-deficient mice exhibited diminished GBS ascension and dissemination. Similarly, the administration of a blocking antibody against the IL-10 receptor (IL-10R) in WT mice diminished ascending GBS infection. Collectively, these observations indicate that HylB promotes immune suppression in a TLR2/4- and IL-10-dependent manner to enhance the invasive potential of GBS during pregnancy-associated infections. IMPORTANCE Bacteria such as GBS can cause infections during pregnancy leading to preterm births, stillbirths, and neonatal infections. The interaction between host and bacterial factors during infections in the placenta is not fully understood. GBS secretes a hyaluronidase enzyme that is thought to digest host hyaluronan into immunosuppressive disaccharides that dampen TLR2/4 signaling, leading to increased bacterial dissemination and adverse outcomes. In this study, we show that GBS HylB mediates immune suppression and promotes bacterial infection during pregnancy that requires TLR2, TLR4, and IL-10. Understanding the interaction between host and bacterial factors can inform future therapeutic strategies to mitigate GBS infections.

Dataset Information

IL-10 Deficiency Reveals a Role for TLR2-Dependent Bystander Activation of T Cells in Lyme Arthritis.

Publications

IL-10 Deficiency Reveals a Role for TLR2-Dependent Bystander Activation of T Cells in Lyme Arthritis.

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