TL1A Induces TCR Independent IL-6 and TNF-α Production and Growth of PLZF+ Leukocytes

Reichwald, Kirsten; Jørgensen, Tina Z.; Tougaard, Peter; Skov, Søren

doi:10.1371/journal.pone.0085793

Cited by 16 publications

(19 citation statements)

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“…In addition, aberrant expression of NKG2D or its ligands on IELs is associated with various gut‐related inflammatory diseases, such as Crohn's and coeliac diseases . The decrease in NKG2D on IEL subsets in TL1A KO mice is in accordance with in vitro stimulation studies we have performed, showing that stimulation with TL1A specifically induce the upregulation of NKG2D on human peripheral blood lymphocytes (PBLs) . Thus, less NKG2D expression indicates that the IELs in the TL1A KO mice are less capable of detecting stress in the surrounding epithelial cells than WT mice.…”

Section: Discussionsupporting

confidence: 76%

TL1A regulates TCRγδ⁺ intraepithelial lymphocytes and gut microbial composition

et al. 2014

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TL1A is a proinflammatory cytokine, which is prevalent in the gut. High TL1A concentrations are present in patients with inflammatory bowel disease (IBD) and in IBD mouse models. However, the role of TL1A during steady-state conditions is relatively unknown. Here, we used TL1A knockout (KO) mice to analyse the impact of TL1A on the intestinal immune system and gut microbiota. The TL1A KO mice showed reduced amounts of small intestinal intraepithelial TCRγδ + and CD8 + T cells, and reduced expression of the activating receptor NKG2D. Moreover, the TL1A KO mice had significantly reduced body weight and visceral adipose tissue deposits, as well as lower levels of leptin and CXCL1, compared with wild-type mice. Analysis of the gut microbial composition of TL1A KO mice revealed a reduction of caecal Clostridial cluster IV, a change in the Firmicutes/Bacteroidetes ratio in caecum and less Lactobacillus spp. in the mucosal ileum. Our results show that TL1A deficiency impacts on the gut microbial composition and the mucosal immune system, especially the intraepithelial TCRγδ + T-cell subset, and that TL1A is involved in the establishment of adipose tissue. This research contributes to a broader understanding of TL1A inhibition, which is increasingly considered for treatment of IBD.Keywords: γδ T cells r Gut microbiota r Intraepithelial lymphocytes (IELs) r NKG2D r TL1A Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Peter Tougaard e-mail: peto@sund.ku.dk IntroductionAn increased production of proinflammatory cytokines is associated with the development of adiposity. The consequential impact of increased cytokine levels is especially pronounced in abdominal adipose tissue, and in the gut, and causes a chronic C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 866Peter Tougaard et al. Eur. J. Immunol. 2015. 45: 865-875 state of low-grade inflammation in the host [1,2]. This inflammatory state is associated with changes in the gut epithelial functions, composition of the gut microbiota and gut immune homeostasis [2][3][4]. TNF-α and other TNF family cytokines have especially been associated with this low-grade inflammatory state [2,4,5]. However, further studies about these cytokines and their role in low-grade inflammation are required. The proinflammatory cytokine TL1A is emerging as a new important player of the TNF superfamily. TL1A is prevalent in the intestine and tightly connected to inflammatory diseases of the gut, i.e. inflammatory bowel disease (IBD) [6][7][8]. However, the influence of TL1A on gut microbiota composition and low-grade inflammation remains elusive. TL1A is expressed by several different cell types, including endothelial cells and myeloid cells, such as dendritic cells and macrophages [6,9]. Multiple bacterial species from the gut have been shown to directly induce TL1A expression in monocytes and monocyte-derived dendritic cells [10]. The TL1A receptor, death receptor 3 (DR3), is primarily expre...

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Section: Discussionsupporting

confidence: 76%

TL1A regulates TCRγδ⁺ intraepithelial lymphocytes and gut microbial composition

et al. 2014

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“…In combination with IL-12 and IL-18, TL1A supports IFN-γ production by T cells and NK cells [10], and induces proliferation of human NK, NKT and other T cells in vitro [11]–[14]. We have recently shown that TL1A together with IL-12, IL-15 and IL-18 induces IL-6 and TNF-α production in leukocytes purified from healthy donors [12].…”

Section: Introductionmentioning

confidence: 99%

TL1A Increases Expression of CD25, LFA-1, CD134 and CD154, and Induces IL-22 and GM-CSF Production from Effector CD4 T-Cells

2014

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Elevated levels of the cytokine TL1A is associated with several autoimmune diseases e.g. rheumatoid arthritis and inflammatory bowel disease. However, the exact role of TL1A remains elusive. In this study, we investigated the function of TL1A in a pro-inflammatory setting. We show that TL1A together with IL-12, IL-15 and IL-18 increases expression of the co-stimulatory molecules CD154 (CD40 ligand) and CD134 (OX40) on previously activated CD4+ T cells. This indicates that TL1A functions as a co-stimulatory molecule, decreasing the activation threshold of T-cells. We have previously shown that TL1A co-stimulation strongly induces IL-6 in human healthy leukocytes. Interestingly, the cytokine-activated effector T-cells did not produce IL-6 in response to TL1A, indicating distinct effects of TL1A on different cell populations. We further show that this co-stimulation increases the expression of CD25 (IL-2Rα) and CD11a (α-chain of LFA-1) on CD4 T-cells, likely governing increased IL-2/IL-15 sensitivity and cell-cell contact. Along with this, TL1A co-stimulation caused a specific induction of IL-22 and GM-CSF from the activated T-cells. These results substantially contribute to the explanation of TL1A's role in inflammation. Our results suggest that TL1A should be considered as a target for immunotherapeutic treatment of rheumatoid arthritis and inflammatory bowel disease.

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“…We have recently shown that stimulation of PBMCs with TL1A in combination with IL‐12 + IL‐18 has a synergistic effect on proliferation and secretion of other inflammatory cytokines, such as TNF‐α and IL‐6 . Here, the impact of the different cytokines on cellular activation is illustrated both by a representative healthy donor (Fig.…”

Section: Resultsmentioning

confidence: 88%

“…TCR‐independent activation of T cells with cytokines, such as IL‐12 and IL‐18, is a relatively new approach in terms of chronic inflammatory diseases. We recently found that in vitro addition of TL1A to (IL‐12 and IL‐18)‐stimulated lymphocytes, yielded TL1A‐specific expression of TNF‐α and IL‐6 as well as increased proliferation . Such cytokine induced activation, specifically induce proliferation of memory T cells, NK cells and NKT cells.…”

Section: Discussionmentioning

confidence: 99%

Secretion, blood levels and cutaneous expression of TL1A in psoriasis patients

Pedersen

Schmidt

Sørensen

et al. 2015

APMIS

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TL1A is a TNF-like cytokine which has been shown to co-stimulate TH1 and TH17 responses during chronic inflammation. The expression of this novel cytokine has been investigated in inflammatory disorders like rheumatoid arthritis and inflammatory bowel disease, but little is known about expression and induction in psoriasis. Indeed, the pathogenesis in psoriasis is still not fully understood and it is speculated that cytokines other than TNF-α are important in subsets of patients. Also, for patients with severe disease that are treated with systemic anti-TNF-α blockade, novel candidates to be used as disease and response biomarkers are of high interest. Here, we demonstrate TL1A expression in biopsies from psoriatic lesions. Also, we investigated spontaneous and induced TL1A secretion from PBMCs and blood levels from a cohort of psoriasis patients. Here, increased spontaneous secretion from PBMCs was observed as compared to healthy controls and a small subset of patients had highly elevated TL1A in the blood. Interestingly, activation of PBMCs with various cytokines showed a decreased sensitivity for TL1A activation in psoriasis patients compared to healthy controls.TL1A levels in blood and biopsies could not be correlated with disease activity with this patient cohort. Thus, additional large-scale studies are warranted to investigate TL1A as a biomarker.

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TL1A Induces TCR Independent IL-6 and TNF-α Production and Growth of PLZF+ Leukocytes

Cited by 16 publications

References 58 publications

TL1A regulates TCRγδ⁺ intraepithelial lymphocytes and gut microbial composition

TL1A regulates TCRγδ⁺ intraepithelial lymphocytes and gut microbial composition

TL1A Increases Expression of CD25, LFA-1, CD134 and CD154, and Induces IL-22 and GM-CSF Production from Effector CD4 T-Cells

Secretion, blood levels and cutaneous expression of TL1A in psoriasis patients

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TL1A Induces TCR Independent IL-6 and TNF-α Production and Growth of PLZF+ Leukocytes

Cited by 16 publications

References 58 publications

TL1A regulates TCRγδ+ intraepithelial lymphocytes and gut microbial composition

TL1A regulates TCRγδ+ intraepithelial lymphocytes and gut microbial composition

TL1A Increases Expression of CD25, LFA-1, CD134 and CD154, and Induces IL-22 and GM-CSF Production from Effector CD4 T-Cells

Secretion, blood levels and cutaneous expression of TL1A in psoriasis patients

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TL1A regulates TCRγδ⁺ intraepithelial lymphocytes and gut microbial composition

TL1A regulates TCRγδ⁺ intraepithelial lymphocytes and gut microbial composition