Healthy cells in the lining of the intestine are crucial in protecting internal organs from infectious pathogens that reside in the digestive system. However, dysfunction of these cells can lead to inflammatory bowel disease (IBD), a major risk factor for the development of colorectal cancer (CRC).
A study by researchers from the University of Chicago published in the journal Nature identified a critical process that helps intestinal epithelial cells (IECs) stop normal immune cells from becoming overactive and damaging the intestine, thus preventing the development of IBD and CRC.
Healthy gut epithelial cells prevent pathogenic inflammation
The digestive tract is loaded with a variety of bacteria, mostly beneficial ones that help the body digest food and process nutrients. The IECs in the gut have two major functions: one to absorb nutrients and water, and another to provide a barrier between microbes in the gut and the host immune cells.
The body’s immune response is triggered when IECs carry signals from harmful, pathogenic microbes or their metabolites and present them as antigens to the host immune cells. This process is crucial to maintain a healthy balance between gut microbes and the immune system and prevent the growth of pathogenic microbes.
The major type of immune cells that respond to pathogenic antigens in the gut are called differentiation 4 positive (CD4+) T-cells. Although these cells are essential to eliminate pathogens, unregulated activity of CD4+ T-cells can cause inflammation in the intestine and lead to the development of IBD. However, the process by which CD4+ T-cells cross the line and become dangerous is not well studied.
IECs regulate CD4+ T-cells via IFNγ signaling
Researchers in the lab of Bana Jabri, MD, PhD, the Sarah and Harold Lincoln Thompson Distinguished Service Professor in the Departments of Medicine, Pathology, and Pediatrics, and Chair of the Committee on Immunology, conducted studies in mice to understand how healthy IECs are able to control the function of CD4+ T-cells and how IEC dysfunction can lead to pathogenic CD4+ T-cells.
The adaptive immune system “remembers” foreign pathogens that it has encountered in the past. When it recognizes their antigens again, genes in the major histocompatibility complexes (MHC) class I (MHC I) and class II (MHC II) express molecules in response, including a cytokine called interferon-gamma (IFNγ). Single nucleotide polymorphisms (SNPs), or mutations, in the receptor for IFNγ (IFNγR) are significantly associated with the development of IBD and CRC, however, the mechanisms behind the development of disease remain unknown.
“We want to evaluate the role of epithelial IFNγ signaling in colitis, so we tested IEC-specific IFNγR deficient mice by orally infecting them with colitis-causing bacteria, Citrobacter rodentium, to mimic the acute colitis condition in humans,” said Ankit Malik, PhD, Research Associate at UChicago and first and co-corresponding author of the study.
With infection of C. rodentium, the levels of IFNγ were initially raised in the colon but came back to normal three weeks after infection. IFNγR1-deficient mice developed severe colitis, however, and colon histology was worse, indicating IFNγ signaling is critical to limit the inflammation from pathogenic infection.
Antigen presentation by IECs is essential for colorectal cancer prevention
The researchers showed that, upon sensing IFNγ, IECs present antigens to CD4+ and CD8+ T-cells located nearby at the epithelial barrier. This increases T-cell activity, which limits inflammation caused by tissue macrophages. In contrast, when tissue macrophages present antigens alongside other inflammatory molecules, it stimulates CD4 +T cells to transform into their more overactive, pathogenic form, promoting colitis and colorectal cancer.
“Supporting the relevance of these findings in humans, we show that the IBD-associated IFNγR SNP leads to defective IFNγ signaling. Furthermore, decreased expression of IFNγR or ATPase and increased expression of granulocyte macrophage colony-stimulating factor (GM-CSF) are associated with IBD that is resistant to the standard therapies, and reduced survival with colorectal cancer,” said Malik.
The study highlights a critical checkpoint requiring IFNγ sensing and antigen presentation by IECs to control the development of pathogenic CD4 +T cell responses. “It puts forward a model wherein a balanced immune response, finetuned by IFN-g, controls inflammation and cancer in the gut. It also provides novel targets for intervention in IBD and supports the concept of precision therapy, wherein the therapeutic interventions are based on the patient’s underlying genetic makeup and nature of inflammation,” Jabri said.
The study “Epithelial IFNγ signalling and compartmentalized antigen presentation orchestrate gut immunity” was supported by grants from the National Institutes of Health, The University of Chicago’s Center for Interdisciplinary Study of Inflammatory Intestinal Disorders Pilot & Feasibility Award, Crohn’s and Colitis Foundation Career Development Award and a G.I. Research Foundation Associates Board Award.
Additional authors include Deepika Sharma, Raúl Aguirre-Gamboa, Shaina McGrath, Sarah Zabala, and Christopher Weber from the University of Chicago.
