T cells are immune cells that drive the development of inflammatory bowel disease (ulcerative colitis and Crohn’s disease) through the way that they react to the bacteria that are resident in our gut.
Until recently it was thought that T cells continuously enter and leave the gut via the bloodstream but a new type of T cell has been found that resides in the gut for extended periods of time. This type of T cell is known as a resident memory T cell or Trm.
This PhD study, funded by the Masonic Charitable Foundation has three aims:
- To identify and characterise Trm in the gut of patients with IBD and a healthy control group;
- to determine the contribution to inflammation of Trm in patients with IBD; and
- to relate Trm function to outcomes following therapy.
The researchers
The research will be led by Professor James Lindsay and Dr Andrew Stagg at Queen Mary University of London. The work will be undertaken day-to-day by a PhD student.
Why analyse the role of T cells in inflammatory bowel disease?
Inflammatory bowel disease (IBD; Crohn’s disease and ulcerative colitis) is a lifelong, debilitating and sometimes life-threatening condition. It is caused by an uncontrolled immune response to aspects of the bacteria that reside within the gut.
Genes play a role in making an individual susceptible to the condition as does the environment (diet, exercise, pollution, infection etc.) but this is currently poorly understood.
There are around 300,000 IBD patients in the UK, and 1 in 20 of these suffer from a severe form of the disease that dominates their life. Most people will be first diagnosed in adolescence.
IBD is expensive to treat and the average lifetime cost of treating an IBD patient is comparable to that of a patient with coronary heart disease or cancer, costing the NHS over £500 million each year. There is no cure for IBD and control of inflammation with drugs or surgical removal of affected tissue are often not satisfactory over the long term.
Biological therapies targeting immune responses have had a major impact on treatment, and approximately 30,000 UK patients are currently receiving a biologic, which now accounts for 75% of healthcare costs. However, up to one third of patients do not respond and a similar proportion lose response over time. The failure of some therapies for particular patients is likely to be related to differences in how their individual immune responses react (immune pathways).
This work will help us to further our understanding of the immune pathways that drive intestinal inflammation and how these vary between individual patients with either Crohn’s disease or Ulcerative Colitis. Our aim is therefore to increase personalisation in therapies for individuals with IBD and to bring down the costs to the NHS of treating the lifelong effects of the condition.
We are very grateful to the Masonic Charitable Foundation, which is funding this study over three years.
Final Report Summary
T cells within the intestinal mucosa play a key role in the dysregulated immune response to the intestinal microbiota that is the cause of inflammatory bowel disease (IBD). Recently, tissue-resident memory T cells (Trm) have been identified in the human intestinal mucosa that are maintained for long periods of time, independent of circulating T cells. These Trm provide rapid immune protection but in animal models can also contribute to intestinal inflammation. The overall aim of this study is to understand the role of Trm in human IBD and the factors that shape their development and function.
Using flow cytometry analysis, it was determined that the majority of intestinal T cells were Trm in both health and IBD; there was no evidence for a major population of recruited non-resident cells in inflamed tissue. However, scRNAseq revealed that Trm in inflamed tissue were transcriptionally distinct, upregulating genes associated with activation and immune function but downregulating pathways linked to lipid metabolism. They had enhanced expression of genes associated with tissue egress, suggestive of a transitional population less committed to residency.
Recently the exit of Trm from the skin has been described, generating a population of functionally plastic, circulating ex-Trm with capacity to return selectively to their tissue of origin and promote inflammation. Here, a candidate equivalent population derived from the intestine was identified for the first time. These putative gut ex-Trm were increased in frequency and transcriptionally altered in treatment-naïve Crohn’s disease patients, with evidence for enhanced inflammatory activity. We speculate that these cells link discrete areas of inflammation in Crohn’s disease.
The aryl hydrocarbon receptor (AHR), a key environmental sensor linking to the immune system, was expressed by Trm in intestinal tissues, leading us to hypothesise that AHR ligands shape the development and function of Trm. To test this, an in vitro model of Trm generation was developed and used to observe that Trm generation was enhanced by an AHR agonist and inhibited by an AHR antagonist. Interestingly, gut-tropic memory T cells uniquely had an active AHR signalling pathway and also generated more Trm than did naïve T cells or memory T cells with other homing trajectories. Soluble factors obtained from cultured intestinal tissue did not, on their own, induce Trm additional undefined signals must be required.
These findings suggest that T cells that acquire long-term residence in the intestine can contribute to inflammation in IBD. The signals that influence their development, survival and function may offer new therapeutic targets. Understanding the relative contribution of resident and recruited cells in individual IBD patients may lead to biomarkers that predict response to therapies targeting lymphocyte recruitment. The newly identified putative occur ex-Trm population may shed light on the maintenance of inflammation at different intestinal sites.
Impact of Bowel & Cancer Research funding
Funding from Bowel & Cancer Research/Bowel Research UK has made this study possible. Without support for a PhD student, it would not have happened. Thus, the funding has supported the development of a translational immunologist interested in IBD, who we hope will go on to make other contributions to the field. Data generated in this project was a key element of preliminary work forming part of significant further grant applications that we hope will support a clinical fellow in the field of IBD.