TL1A regulates TCRγδ⁺ intraepithelial lymphocytes and gut microbial composition

Abstract

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...

Chronic Inflammation and γδ T Cells

“…Inflammatory mediators are likely to impact γδ IEL function in the intestine. TNF-like protein 1A (TL1A) is a pro-inflammatory cytokine from the TNF cytokine family, which is found in high concentrations in mouse models of inflammatory bowel disease (IBD) ( 17 ). TL1A knockout mice exhibit fewer γδ IELs as compared to wild-type mice ( 17 ).…”

The small bowel microbiota

“…It is, therefore, worth noting that the mucosal microbiota in the murine ileum was found to differ in TLA1 knockout mice when compared with wild-type controls [65], reaffirming that altered host immunity can lead to an altered intestinal microbiota. It is, therefore, worth noting that the mucosal microbiota in the murine ileum was found to differ in TLA1 knockout mice when compared with wild-type controls [65], reaffirming that altered host immunity can lead to an altered intestinal microbiota.…”

Breastfeeding and the gut-brain axis: is there a role for melatonin?

“…Consequently, as well as breastfeeding modulating infant gamma-delta T cells responses, breastfeeding may also epigenetically regulate the nature of gamma-delta T cell interactions with the adaptive immune system over the lifespan (79). It requires investigation as to whether this is mediated by alterations in the levels and/or regulation of the TNF-like cytokine TL1A, which is highly expressed in the gut (80), where it acts to regulate mucosal Th1, Th2, Th17 and regulatory T cells (81,82) as well as gamma-delta T cells and the microbiome (80). The induction of TL1A is via the activation of the transcription factor, nuclear factor-kappa B (NF-kB) (83), suggesting that the numerous factors that act to regulate NF-kB in breast milk, including melatonin (84), DHA (85) and NGF (86), may directly, or via the growth of an optimized microbiome, act to regulate TL1A.…”