TNF-α blockade induces IL-10 expression in human CD4+ T cells

Evans, Hayley G.; Roostalu, Urmas; Walter, Gina; Gullick, Nicola; Frederiksen, Klaus Stensgaard; Roberts, Ceri A.; Sumner, Jonathan; Baeten, Dominique; Gerwien, Jens; Cope, Andrew P.; Geissmann, Frédéric; Kirkham, Bruce; Taams, Leonie S.

doi:10.1038/ncomms4199

Cited by 104 publications

(120 citation statements)

References 59 publications

(69 reference statements)

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“…9a, b), and in addition to this, mice lacking Blimp1 specifically in T cells exhibited significantly higher levels of serum TNF, antigen-specific TNF production, as well as higher frequencies of TNF-producing CD4 + T cells in both the spleen and liver (Fig 2e, 3e, 4a, 4c). A recent study demonstrated that TNF blockade induced IL-10 expression in human CD4 + T cells 382 , supporting earlier reports of IL-10 mediated regulation of TNF 383,384,385 .…”

Section: Blimp1 Deficiency In Treg Cells Does Not Influence Parasite supporting

confidence: 66%

Regulation of CD4+ T cell responses during parasitic infections

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observed a significant increase in TNF producing CD4 + T cells in the T cell specific Blimp1 deficient mice which was associated with extensive splenomegaly, a characteristic feature observed in patients with visceral leishmaniasis (VL). Importantly, Blimp1 transcripts were also found to be up-regulated in VL patients, indicating the clinical relevance of Blimp1 during infection. We sought to determine the mechanism by which Blimp1 was regulating pathology in the spleen. Firstly, we confirmed that the loss of MZM's in the T cell specific Blimp1 deficient mice was due to a lack of IL-10, where T cell-specific IL-10 deficient mice also displayed the same phenotype of MZM loss, and this process appeared to be TNF dependent. In support of IL-10 mediating protection against MZM loss, we were able to show that IL-10 signalling in T cells and myeloid-derived populations was a requirement for protection against TNF-mediated destruction. In summary, our data reveals a novel mechanism where Blimp1 induced IL-10 production by Tr1 cells limits pathology during infection. These findings have wider implications for other inflammatory diseases. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School.I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis.

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Section: Blimp1 Deficiency In Treg Cells Does Not Influence Parasite supporting

confidence: 66%

Regulation of CD4+ T cell responses during parasitic infections

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“…The transcription factor IKZF3/ Aiolos is upregulated in Th17 cells upon TNF inhibition [75]. IKZF3 expression correlates with IL-10 expression in these cells and overexpression of IKZF3 in CD4+ T cells upregulates IL-10 [75]. Collectively, these data suggest that interruption of TNFα signalling induces IKZF3 in Th17 cells resulting in increased expression of IL-10.…”

Section: What Is the Primary Source Of Il-17 In Pso And Psa?mentioning

confidence: 83%

“…IL-10 expression is increased in human Th17 cells following in vitro culture with TNFα inhibitors and in vivo on commencement of TNF inhibitor therapy [75]. The transcription factor IKZF3/ Aiolos is upregulated in Th17 cells upon TNF inhibition [75]. IKZF3 expression correlates with IL-10 expression in these cells and overexpression of IKZF3 in CD4+ T cells upregulates IL-10 [75].…”

Section: What Is the Primary Source Of Il-17 In Pso And Psa?mentioning

confidence: 98%

“…Human Th17 cells also demonstrate the potential to adopt an immunosuppressive phenotype. IL-10 expression is increased in human Th17 cells following in vitro culture with TNFα inhibitors and in vivo on commencement of TNF inhibitor therapy [75]. The transcription factor IKZF3/ Aiolos is upregulated in Th17 cells upon TNF inhibition [75].…”

Section: What Is the Primary Source Of Il-17 In Pso And Psa?mentioning

confidence: 99%

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Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis

2015

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Investigators have accrued compelling evidence that the IL-17 pathway is central to the pathogenesis of psoriasis and psoriatic arthritis. The evidence comprises genome-wide association studies (GWAS), data from experimental murine models and findings from in vitro studies on patients' cells or tissue biopsies. More recently, the success of drugs blocking the IL-17 pathway in treating both psoriasis (PsO) and psoriatic arthritis (PsA) confirms that IL-17 is a clinically relevant therapeutic target. However, there remain many unanswered questions: is PsA simply an extension of PsO from the skin to the synovial tissue or are there differences in the underlying pathogenesis of these diseases? Which cell type represents the primary source of IL-17 in PsO and PsA? And how are these cells regulated? This review outlines the IL-17 pathway, summarises the evidence supporting its role in PsO and PsA and discusses recent data that may help to address these yet unresolved questions.

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“…Unexpectedly, these T cells did not have typical Treg markers; therefore TNF-α blockade may also act by promoting suppressor function in non-Treg CD4 + populations [78]. Recent human studies have reflected this finding, showing that TNF-α blockers can induce immunosuppressive features in Th17 cells [79]. …”

Section: Translation From Mouse To Humanmentioning

confidence: 99%

Histoplasma Capsulatum , Lung Infection and Immunity

2015

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Histoplasma capsulatum, an environmental fungus, is the most common endemic pulmonary mycosis in the USA. Disease is most frequently observed in immunocompromised patients living in endemic areas. We present the mechanisms of fungal recognition, innate immune response and adaptive immune response that lead to protection or exacerbation of disease. Current understanding of these mechanisms is the result of a continuing dialogue between clinical observations and murine studies. Mice are a powerful model to study the immune response to H. capsulatum alone or in the presence of immunomodulatory drugs. Vigilance for histoplasmosis should be exercised with novel immunosuppressive agents that target the important immune pathways identified here.

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TNF-α blockade induces IL-10 expression in human CD4+ T cells

Cited by 104 publications

References 59 publications

Regulation of CD4+ T cell responses during parasitic infections

Regulation of CD4+ T cell responses during parasitic infections

Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis

Histoplasma Capsulatum , Lung Infection and Immunity

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