A previously unknown immune regulatory network that equips the intestine to fend off harmful bacteria has been uncovered by researchers at the BRIC–National Institute of Immunology, New Delhi. The study1 identifies the immune regulator RelB as a key controller of specialised dendritic cells that coordinate protective responses in the gut.
The intestine must strike a delicate balance between tolerating beneficial microbes and rapidly responding to invading pathogens. Dendritic cells orchestrate this defence by producing signalling molecules that activate protective immune responses, but the mechanisms controlling these cells have remained incompletely understood.
Using genetically engineered mice infected with the intestinal pathogen Citrobacter rodentium, the researchers led by Soumen Basak found that deleting RelB from dendritic cells crippled the gut's immune response. Mice lacking RelB produced less IL-23, a signalling molecule that stimulates immune cells to release IL-22, which in turn activates antimicrobial genes in the intestinal lining. As a result, the animals became more susceptible to bacterial infection.
The researchers, including Naveen Kumar, Alvina Deka, Swapnava Basu, Ashish Kumar Mishra and Deepakshi Sahu, traced the defect to an interaction between RelB and the Notch2 signalling pathway. RelB boosted Notch2 activity, enabling the development and maintenance of a rare population of dendritic cells that reside in isolated lymphoid tissues of the intestine and serve as the principal source of IL-23 during infection.
Administering IL-23 restored antibacterial immunity in RelB-deficient mice, confirming the pathway's central role. The findings reveal a previously unrecognised mechanism that links two major immune signalling pathways to gut defence and could inform future therapies for intestinal infections and inflammatory bowel disease.
