Immune Responses in the Intestine
The intestine is a challenging environment for the immune system, which must remain silent against the trillions of bacteria that line the gut but mount rapid responses against pathogens. Specific mechanisms are therefore required to control intestinal immunity, with breakdown in these mechanisms leading to inflammatory bowel disease. Work in our laboratory focuses on how immunity is regulated in the gut to prevent harmful inflammation.
Our recent work has identified a crucial pathway by which intestinal T-cell responses are regulated during health, infection and inflammation. Thus, specialised dendritic cells (DCs) in the gut promote immune tolerance via expression of the integrin αvβ8, which enables them to activate high levels of the cytokine TGFβ. Enhanced TGFβ activation enables the DCs to induce regulatory T-cells (Tregs), a specialised subset of T-cells that suppress self-harmful immune responses. Disruption of this pathway results in inflammatory bowel disease in animal models, highlighting a vital anti-inflammatory pathway in the intestine.
We have also found that this integrin-mediated activation of TGFβ by DCs is important in regulating type 2 immune responses during infection, and also driving autoimmune responses by inducing Th17 cells. Thus, this pathway appears central to the control of both pro- and anti-inflammatory immune responses in the intestine during health and infection. We have also recently found that Tregs themselves, when in an inflammatory environment, activate TGFβ via integrin αvβ8 in order to dampen ongoing T-cell-mediated inflammation. Our current work aims to determine how TGFβ activation by DCs and Tregs occurs, and how this is controlled by the intestinal environment, and how these pathways are altered in human inflammatory bowel disease. We therefore hope to build a detailed cellular and molecular understanding of how DCs and Tregs control T-cell responses to control gut inflammation, which will potentially highlight important checkpoints that can be targeted to prevent inflammatory disorders.
Worthington JJ, Kelly A, Smedley C, Bauché D, Campbell S, Marie JC, Travis MA (2015). Integrin αvβ8-mediated TGFβ activation by effector regulatory T-cells is essential for suppression of T-cell-mediated inflammation. Immunity, 42, 903-915.
Travis MA & Sheppard D (2014). TGF-β activation and function in immunity. Annual Review of Immunology, 32, 51-82.
Worthington JJ, Klementowicz JE, Rahman S, Czajkowska BI, Smedley C, Waldmann H, Sparwasser, T, Grencis RK, Travis MA (2013). Loss of the TGFβ-Activating Integrin αvβ8 on Dendritic Cells Protects Mice from Chronic Intestinal Parasitic Infection via Control of Type 2 Immunity. PLoS Pathogens, 10, 9, 9(10): e1003675.
Worthington JJ, Czajkowska BI, Melton AC, Travis MA (2011). Intestinal dendritic cells specialize to activate transforming growth factor-β and induce Foxp3+ regulatory T cells via integrin αvβ8. Gastroenterology. 141(5):1802-12.
Melton AC, Bailey-Bucktrout SL, Travis MA, Fife BT, Bluestone JA, Sheppard D (2010). αvβ8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice. Journal of Clinical Investigation, 120, 4436-44.
Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, Wang Y, Bernstein X, Huang X, Reichardt LF, Bluestone JA, Sheppard D (2007). Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice. Nature. 20;449(7160):361-5.