An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development

Abstract

The development of inflammatory diseases depends on complex interactions between several genes and various environmental factors. Discovering new genetic risk factors and understanding the mechanisms whereby they influence disease development is of paramount importance. We previously reported that deficiency in Themis1, a new actor of TCR signaling, impairs regulatory T cell (Treg) function and predisposes Brown–Norway (BN) rats to spontaneous inflammatory bowel disease (IBD). In this study, we reveal that the epistasis between Themis1 and Vav1 controls the occurrence of these phenotypes. Indeed, by contrast with BN rats, Themis1 deficiency in Lewis rats neither impairs Treg suppressive functions nor induces pathological manifestations. By using congenic lines on the BN genomic background, we show that the impact of Themis1 deficiency on Treg suppressive functions depends on a 117-kb interval coding for a R63W polymorphism that impacts Vav1 expression and functions. Indeed, the introduction of a 117-kb interval containing the Lewis Vav1-R63 variant restores Treg function and protects Themis1-deficient BN rats from spontaneous IBD development. We further show that Themis1 binds more efficiently to the BN Vav1-W63 variant and is required to stabilize its recruitment to the transmembrane adaptor LAT and to fully promote the activation of Erk kinases. Together, these results highlight the importance of the signaling pathway involving epistasis between Themis1 and Vav1 in the control of Treg suppressive function and susceptibility to IBD development.

Transmaternal Helicobacter pylori exposure reduces allergic airway inflammation in offspring through regulatory T cells

“…Among the differentially expressed genes were genes of the TGF-b signaling pathway (Tgfbi and Smad3), the IL-10 receptor a chain (Il10ra), several genes that had previously been linked to Treg cells found in visceral adipose tissue (Ccr1 and Cd36), and several genes known to be involved in Treg cell functionality and suppressive activity (Themis2 and Runx3; see Fig E6, E). [37][38][39] We conclude from these data that epigenetic marks leading to stable expression of Foxp3 and the definitive lineage commitment of Treg cells, along with differential gene expression caused by extract exposure, reflect and likely mediate the suppressive effects of H pylori-specific perinatal interventions on allergic airway inflammation.…”

Proteomic Analysis of Regulatory T Cells Reveals the Importance of Themis1 in the Control of Their Suppressive Function

“…Alternatively, it could be hypothesized that the positive effect of Themis1 on Vav1 may be preponderant in these cells, and may counterbalance potential inhibitory function of Themis1 through SHP-1. Supporting this interpretation, we previously showed that the combined deficiency of Themis1 and Vav1 in Brown-Norway rats impairs the suppressive function of Treg, despite normal levels of Foxp3 expression, and leads to the spontaneous development of IBD (54,55). This highlights that the cooperation between Themis1 and Vav1 is required for proper Treg function.…”

Interpretable network-guided epistasis detection

“…In the past, several genetic studies have investigated epistasis on IBD [ 6 , 7 , 9–11 , 25 ]. We compared them to our results at the gene level, the minimal functional unit at which we expect genetic studies to converge.…”