Connecting Intestinal and Liver Disease: Colitis Promotes a Pathological Condition of the Liver in the Absence of Foxp3+ Regulatory T Cell

*Based on: Franziska Mathies, Niklas Steffens, Doerte Kleinschmidt, Friederike Stuhlmann, FrancisJ. Huber, Urmi Roy, Thomas Meyer, Marc Luetgehetmann, Mareike vonPetersdorff, Oliver Seiz, Johannes Herkel, Christoph Schramm, Richard Flavell, Nicola Gagliani, Christian Krebs, Ulf Panzer, ZeinabAbdullah, Till Strowig, Tanja Bedke,Samuel Huber. Colitis Promotes a Pathological Condition of the Liver inthe Absence of Foxp3+ Regulatory T Cells. The Journal of Immunology Nov. 16, 2018, ji1800711; DOI: 10.4049/jimmunol.1800711

Regulatory T cells (Tregs) are a subpopulation of T cells that regulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. They are immunosuppressive and down-regulate proliferation of effector T cells. Effector T cells are a type of T cell that respond immediately to a stimulus. Tregs express certain biomarkers, which are measurable substances in an organism whose presence is indicative of some phenomenon such as disease, infection, or environmental exposure.  One of these biomarkers is Foxp3⁺. T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17. They are related to Tregs as the signal that causes Th17 cells to differentiate, actually inhibits Treg differentiation.

Inflammatory bowel disease (IBD) is associated with extra-intestinal diseases, meaning occurring outside the intestines, such as primary sclerosing cholangitis (PSC) in the liver. PSC is a cholestatic liver disease, meaning that there is a reduction or stoppage of bile fluid, that is characterized by inflammation and thickening/scarring of the bile ducts. Roughly 75% of all PSC patients have IBD. It is known that an imbalance between Foxp3⁺ regulatory T cells and Th17 cells is involved in IBD and PSC and that only one mutation in the gene is needed (1). One proposed hypothesis is that intestinal inflammation and barrier defects promote liver disease due to the influx of bacteria and inflammatory cells to the liver. However, despite the known associations, whether inflammatory cells migrate to the liver directly from the intestine remains to be tested and the possible link to Treg and Th17 imbalance is unclear. In addition, it is unclear whether and under which conditions colitis induces a pathological condition of the liver. These are the issues this study attempted to address and used four techniques/tests in two complementary models to do so.

The study found that there was an increased bacterial burden in the liver in mice with colitis, from an increased infiltration of Th17 cells into the liver that had migrated in part from the colon into the liver. Transfer of Th17 cells into mice that lacked Foxp3⁺ Treg caused severe colitis, increased infiltration of Th17 cells into the liver, and an associated pathological condition of the liver. Wild type mice with colitis also developed a pathological condition of the liver upon deletion of Foxp3⁺ Treg. The data highlighted the importance of the Th17-Treg partnership in an IBD-associated pathological condition of the liver.

Overall, the study’s data indicate that colitis can promote a pathological condition of the liver and highlighted an important role of Treg in controlling colitis-associated liver inflammation. The data indicated that acute colitis is associated with increased infiltration of Th17 cells, Foxp3⁺ Tregs, monocytes, and granulocytes in the liver but that this was not accompanied with pathological conditions of the liver. During colitis, Foxp3⁺ Tregs also increase in numbers in the liver and the study hypothesized that Foxp3⁺ Tregs may protect mice against pathological conditions of the liver during colitis. They performed short term depletion of Foxp3⁺ Tregs to confirm. This findings agree with other studies that state that long-term depletion of Foxp3⁺ Tregs also promotes systemic and intestinal inflammation (2).

The data indicated that colitis does not induce pathological conditions of the liver, despite the accumulation of Th17 cells in the liver. However, Foxp3⁺ Tregs are concomitantly recruited to the liver and they found that colitis can induce pathological conditions of the liver in mice with a defect in Foxp3⁺ Tregs. Together, this data supports the notion that Foxp3⁺ Tregs might protect mice from developing pathological conditions of the liver during colitis. The increase of Th17 cells is accompanied by an increase of  Foxp3⁺ Tregs that seem to protect mice from the development of these conditions.

Importance

            The data supports the notion that Th17 cells in the absence of Foxp3⁺ Tregs are in principle able to drive pathological conditions of the liver. The fact that microbes might leak from the colon to the liver because of barrier defects during colitis coincides with the proposal that the liver may act as a “functional vascular firewall” that clears commensals that have penetrated the intestinal vascular circuits (3). Taken all together, the study proposes that IBD might promote liver disease in genetically susceptible patients and therefore, a strict control of IBD activity in these patients would be warranted.

Next Steps

            The presence of Foxp3⁺ Tregs prevents the development of liver inflammation. One possible explanation is that Foxp3⁺ Tregs interfere with bacteria clearance, but future studies to evaluate the impact of Tregs on antibacterial immune responses in colitis associated with pathological conditions of the liver are needed.

            It remains unclear whether colitis actually promotes bystander hepatitis or whether it drives hepatic disease development and progression in genetically susceptible patients. Clarifying this will require further studies combining colitis models, and PSC models in mice.

References

1.     Liu, J. Z.,J. R. Hov, T. Folseraas, E. Ellinghaus, S. M. Rushbrook, N. T. Doncheva, O. A.Andreassen, R. K. Weersma, T. J. Weismu ̈ller, B. Eksteen, et al; InternationalIBD Genetics Consortium. 2013. Dense genotyping of immune-related diseaseregions identifies nine new risk loci for primary sclerosing cholangitis. Nat.Genet. 45: 670–675.

2.     Lahl, K., C.Loddenkemper, C. Drouin, J. Freyer, J. Arnason, G. Eberl, A. Hamann, H. Wagner,J. Huehn, and T. Sparwasser. 2007. Selective depletion of Foxp3+ regulatory Tcells induces a scurfy-like disease. J. Exp. Med. 204: 57–63.

3.     Balmer, M.L., E. Slack, A. de Gottardi, M. A. Lawson, S. Hapfelmeier, L. Miele, A.Grieco, H. Van Vlierberghe, R. Fahrner, N. Patuto, et al. 2014. The liver mayact as a firewall mediating mutualism between the host and its gut commensalmicrobiota. Sci. Transl. Med. 6: 237ra66.