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Regulatory T cells that co-express ROR?t and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4⁺T cells that express ROR?t and IL-17 (T_H17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (T_reg) contribute to T_H17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to T_H17 associated functional plasticity in T_reg. In this study, we investigated the phenotype and functional properties of T_reg in patients with PDAC. We report that PDAC patients have elevated frequency of FOXP3⁺T_reg, which exclusively occurred within the FOXP3⁺ROR?t⁺T_reg compartment. The FOXP3⁺ROR?t⁺T_reg retained FOXP3⁺T_reg markers and represented an activated subset. The expression of ROR?t in T_reg may indicate a phenotypic switch toward T_H17 cells. However, the FOXP3⁺ROR?t⁺T_reg produced both T_H17 and T_H2 associated pro-inflammatory cytokines, which corresponded with elevated T_H17 and T_H2 immune responses in PDAC patients. Both the FOXP3⁺T_reg and FOXP3⁺ROR?t⁺T_reg from PDAC patients strongly suppressed T cell immune responses, but they had impaired anti-inflammatory properties. We conclude that FOXP3⁺ROR?t⁺T_reg have a dual phenotype with combined pro-inflammatory and immunosuppressive activity, which may be involved in the pathogenesis of PDAC.

SUBMITTER: Chellappa S

PROVIDER: S-EPMC4839385 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Regulatory T cells that co-express RORγt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer.

Chellappa Stalin S Hugenschmidt Harald H Hagness Morten M Line Pål D PD Labori Knut J KJ Wiedswang Gro G Taskén Kjetil K Aandahl Einar M EM

Oncoimmunology 20151029 4

Pancreatic ductal adenocarcinoma (PDAC) is highly infiltrated by CD4+T cells that express RORγt and IL-17 (TH17). Compelling evidence from the tumor microenvironment suggest that regulatory T cells (Treg) contribute to TH17 mediated inflammation. Concurrently, PDAC patients have elevated levels of pro-inflammatory cytokines that may lead to TH17 associated functional plasticity in Treg. In this study, we investigated the phenotype ...[more]

PMID: 27141387

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Project description:BackgroundAstrocytes contribute to the crosstalk that generates chronic neuro-inflammation in neurological diseases; however, compared with microglia, astrocytes respond to a more limited continuum of innate immune system stimulants. Recent studies suggest that the fibrinolysis system may regulate inflammation. The goal of this study was to test whether fibrinolysis system components activate astrocytes and if so, elucidate the responsible biochemical pathway.MethodsPrimary cultures of astrocytes and microglia were prepared from neonatal mouse brains. The ability of purified fibrinolysis system proteins to elicit a pro-inflammatory response was determined by measuring expression of the mRNAs encoding tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and chemokine (C-C motif) ligand 2 (CCL2). IκBα phosphorylation also was measured. Plasminogen activation in association with cells was detected by chromogenic substrate hydrolysis. The activity of specific receptors was tested using neutralizing antibodies and reagents.ResultsAstrocytes expressed pro-inflammatory cytokines when treated with plasminogen but not when treated with agonists for Toll-like Receptor-4 (TLR4), TLR2, or TLR9. Microglia also expressed pro-inflammatory cytokines in response to plasminogen; however, in these cells, the response was observed only when tissue-type plasminogen activator (tPA) was added to activate plasminogen. In astrocytes, endogenously produced urokinase-type plasminogen activator (uPA) converted plasminogen into plasmin in the absence of tPA. Plasminogen activation was dependent on the plasminogen receptor, α-enolase, and the uPA receptor, uPAR. Although uPAR is capable of directly activating cell-signaling, the receptor responsible for cytokine expression and IκBα phosphorylation response to plasmin was Protease-activated Receptor-1 (PAR-1). The pathway, by which plasminogen induced astrocyte activation, was blocked by inhibiting any one of the three receptors implicated in this pathway with reagents such as εACA, α-enolase-specific antibody, uPAR-specific antibody, the uPA amino terminal fragment, or a pharmacologic PAR-1 inhibitor.ConclusionsPlasminogen may activate astrocytes for pro-inflammatory cytokine expression through the concerted action of at least three distinct fibrinolysis protease receptors. The pathway is dependent on uPA to activate plasminogen, which is expressed endogenously by astrocytes in culture but also may be provided by other cells in the astrocytic cell microenvironment in the CNS.

Dataset Information

Regulatory T cells that co-express ROR?t and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer.

Publications

Regulatory T cells that co-express RORγt and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer.

Similar Datasets

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