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Kiel researchers show that immune cells targeting Candida albicans most likely originate in the oral mucosa and acquire harmful properties in chronic intestinal inflammation — a new starting point for therapy.
Almost everyone carries Candida albicans. The yeast colonises human mucous membranes — for example the oral mucosa and the intestine — usually silently without causing any problems. The immune system learns early on how to deal with it. It develops specialised immune cells known as Th17 cells, which keep the fungus in check. What exactly these cells do in the healthy body, where they originate from, and why they can become harmful in Crohn's disease has now been systematically uncovered by a research team from the Excellence Cluster "Precision Medicine in Chronic Inflammation" (PMI) at Kiel University. The study was published today in the journal Immunity.
Precise immune defence against a familiar foe
The immune system controls Candida albicans using a specific class of immune cells, the Th17 cells. They patrol human mucous membranes and release signalling molecules that control the fungus. Each of these Th17 cells responds to a specific target, known as an antigen.
The yeast Candida albicans possesses thousands of such potential target structures. One would expect that Th17 cells recognise many of them, resulting in a broad, diversified immune response against a wide range of fungal proteins. Yet the opposite is the case: the Th17 response is directed against a surprisingly small selection of fungal proteins, derived primarily from extracellular vesicles. These are tiny particles that Candida actively releases into its surroundings, essentially serving as signals to the environment. That these vesicles exert such a strong influence on the Th17 response was previously unknown. "We did not expect that the Th17 response against Candida albicans is so focused. The fact that the entire Candida-specific Th17 repertoire concentrates on a handful of proteins from extracellular vesicles was a very surprising finding for us," says Gabriela Rios Martini, first author of the study. This focused response is likely connected to the vesicles themselves. "The mucosal barrier probably acts as a filter: under healthy conditions, it may be primarily the vesicles that can pass through, meaning that probably only these proteins are available to the immune system," says Philipp Hofmann, also a first author of the study.
The oral mucosa as the site of origin?
Until now, it was unclear where exactly these Candida albicans-specific Th17 cells originate. The new findings suggest that the oral mucosa plays an important role in this process. A particularly high number of Th17 cells can be detected there. This is biological plausible: the oral mucosa is a key site of contact between Candida and the human body. The immune system likely encounters the fungus there frequently, which may contribute to the development and activation of corresponding immune responses.
Shared immune cells in the oral mucosa and gut
To investigate whether the same Th17 cells are also present in other parts of the body, the research team analysed the T cell receptors of cells from various tissues. Each T cell receptor is unique and acts like a molecular fingerprint that indicates which antigen a cell recognises. If the same fingerprint appears in two different tissues, it is likely that the cells originate from the same immune response.
The team was able to demonstrate exactly this: identical immune cell clones appear in both the oral mucosa and the intestine. And the most important driver of this overlap appears to be Candida albicans. This suggests that the mouth and gut are immunologically more closely connected than previously assumed.
When control is lost
In healthy individuals, the Candida-specific Th17 cells remain in a stable, regulated state. In the inflamed intestine of Crohn's disease patients, this changes. These cells accumulate in the gut but carry molecular markers indicating that they were initially shaped in the oral mucosa. They are therefore not newly generated cells, but familiar ones in an unfamiliar environment.
However, this new environment alters their behaviour. They retain their original specificity and continue to recognise the same small selection of fungal proteins, but they acquire additional properties associated with a potentially tissue-damaging immune response. What changes is not the target of the immune response, but the way in which it is executed.
A new therapeutic target
The findings open up a new perspective on chronic inflammation in Crohn's disease. Existing therapies often suppress large parts of the immune system. The new findings could in the future enable a more targeted approach.
"Our data suggest that pre-existing, intrinsically homeostatic Th17 cells undergo functional changes in the disease context, rather than newly arising as a consequence of intestinal inflammation," says Prof. Petra Bacher, Director of the Institute for Medical Immunology and senior author of the study. "This provides a concrete starting point for more targeted therapeutic approaches."
Existing biologics may also be able to modulate the altered Th17 cells against Candida albicans. Agents that affect immune cell migration, such as α4β7 integrin antagonists or S1P modulators, could prevent Candida-reactive Th17 cells from accumulating in the intestine. Anti-IL-23 therapies, in turn, may attenuate their inflammatory properties. How these biologic therapies specifically affect this immune cell population will be investigated in further studies.
"This work is an excellent example of translating research findings into the clinic, particularly with regard to the role of Candida. These results also document the special role of immunological research in inflammation medicine," says Prof. Stefan Schreiber, spokesperson of the Excellence Cluster PMI and Director of the Department of Internal Medicine I, UKSH, Campus Kiel, in collaboration with whom the study was conducted.
Prof. Dr. rer. nat. Petra Bacher
UKSH Campus Kiel
Institut für Immunologie
Petra.Bacher@uksh.de
https://doi.org/10.1016/j.immuni.2026.06.013
https://www.precisionmedicine.de/en/immune-response-to-otherwise-harmless-yeast-...
Research Team: Rios Martini, Bacher, Hofmann
Copyright: Susanne Landis
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