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Deep within the intestinal wall, beyond where digestion and nutrient absorption occur, are immune outposts called solitary isolated lymphoid tissues, or SILTs. These structures host cells that govern how aggressively the gut reacts to microbes. A weak response lets pathogens take root while an overactive one causes the immune system to attack the gut — a hallmark of inflammatory disorders like Crohn’s disease.
A new study in Proceedings of the National Academy of Sciences has traced this balancing act to a protein called RelB. By engineering mice lacking RelB in these cells, researchers at the National Institute of Immunology (NII), New Delhi, uncovered a paradox: the same protein drives opposite effects depending on its cellular environment and anatomical niche.
The finding could matter for patients with inflammatory bowel disease because a drug that targets an overactive immune response may also weaken the gut’s ability to fight harmful bacteria. And understanding where RelB is helping or hurting could be important before this pathway is considered for treatment.
The gate-keeper
To execute many of its immune effects, the gut relies on IL-23, a signalling molecule that triggers inflammation to ward off threats.
IL-23 “functions as an alarm system at barrier surfaces such as the gut, skin, and lungs,” Gourishankar Ghosh, a professor of chemistry and biochemistry at University of California San Diego, U.S., said.
In the gut, it sparks a chain reaction that switches on antimicrobial defences. “However, uncontrolled production can drive chronic inflammatory diseases, including psoriasis and inflammatory bowel disease.”
The researchers found RelB is a gatekeeper for this system: it dictates whether the gut can even produce the sentinel dendritic cells residing in SILT outposts to make IL-23. In RelB-deficient mice, this defender population nearly vanished.
Soumen Basak, an immunologist at NII who led the study, explained that earlier research suggested RelB simply helped existing cells pump out IL-23. Faced with the missing cells, the team investigated further.
“We considered two possible explanations: either the absence of … RelB reduced the number of IL-23-producing [dendritic cells] in these mice or simply a lack of RelB impaired the ability of these dendritic cells to make IL-23,” Dr. Basak said.
The study proved the former is the primary culprit.
Known troublemaker
However, RelB does not act as a heroic shield everywhere in the gut. While it builds a protective army in the intestinal wall, it suppresses regulatory T-cells — the immune system’s peacekeepers — in the nearby lymph nodes.
Earlier work from Dr. Basak’s lab found that by shutting down these peacekeepers, RelB worsens chronic intestinal inflammation.
The answer to how a single protein pulls off this Jekyll-and-Hyde routine might lie in the dendritic cells themselves.
Devesha Kulkarni, assistant professor of medicine at University of California, Los Angeles (UCLA), said dendritic cells are “not one fixed cell type” with a single job. Instead, they are shapeshifters that adopt distinct identities based on the tissue they lie in and the local chemical signals.
And now, scientists know RelB helps fix that local identity — a role Dr. Basak said he considers to be a major conceptual leap.
Flipping the switch
The researchers found RelB switches on the production of a second protein, RBP-J. This acts as a key, unlocking a completely different communication network. And only when this connection completes can immature cells develop into the gut’s specialised IL-23-producing sentinels.
The finding reveals a surprising twist: two systems long assumed to operate independently — RelB and the communication network — actually cooperate to arm the gut.
“Making a delicious dish requires the right combination of many ingredients — salt, turmeric, garlic, ginger, and spices,” Dr. Basak said. “Each ingredient contributes a unique flavour, but none can produce the desired taste on its own. Our study emphasises that signalling pathways must also work together in a coordinated manner to generate appropriate cellular and immune responses.”
That said, a deeper mystery remains: how can a single protein act as a brake in one context and an accelerator in another?
Alexander Hoffmann, professor of immunology at UCLA, said the contradiction comes down to competition. RelB, he said, is a relatively weak activator compared to its cousin, RelA, so when both proteins try to access the same gene, the weaker RelB gets in the way.
By blocking RelA’s strong signal, RelB dials down the overall effect so “it seems like a repressor,” Dr. Hoffmann explained.
But on genes that RelA cannot access — like the one that triggers the gut’s defenses — “RelB’s weak activation potential is sufficient to drive gene expression.”
“This new work is a remarkable example of how the Basak lab over many years has developed expertise in dissecting complex networks of interaction,” he added.
Delicate drug target
Drugs that block IL-23 are already frontline treatments for inflammatory bowel disease, making RelB an intriguing but delicate new drug target. Because the protein acts as both guardian and saboteur depending on its neighbourhood, safely targeting it remains a complex challenge.
Saurabh Mehandru, associate professor of Gastroenterology at the Icahn School of Medicine at Mount Sinai, New York, said that because the research used mice, “the findings will need to be extended before they can be read directly into patient care.”
He also pointed to a key gap that Basak’s team has also acknowledged: because the protective cell clusters are almost entirely missing in the modified mice, it is difficult to prove whether RelB is required to build those cells in the first place or simply to keep them alive once they are formed. Future experiments tracking the lifespans of these cells will ultimately settle that debate, Dr. Mehandru added.
Dr. Basak is already looking ahead. His team wants to know if the relay operates at other vulnerable barriers, like the lungs, and whether tweaking it could yield new treatments.
Anirban Mukhopadhyay is a geneticist by training and science communicator from New Delhi.
Published – October 19, 2026 09:00 am IST
