Rare Immune Cells are Key in Mounting a Defence Against Candida
Credit: Edgerton Lab, State University of New York at Buffalo
Candida, a distant cousin of baker’s yeast is notorious for causing various types of thrush that can be a major nuisance, but it can also lead to an invasive and occasionally fatal infection. In a study in the journal Nature Immunology, a research team uncovered a previously unknown defense mechanism employed by the immune system in fighting Candida infections.
In healthy individuals, Candida is present in the microbiome in the gut and on the skin. Normally, Candida is held in check by the immune system, but it can occasionally grow excessively, invading the lining of the mouth, the vagina, the skin or other parts of the body. In severe cases, it can spread to the bloodstream and from there to the kidneys. Such life-threating infections may occur in weakened immune systems. Antibiotics can also unleash local or invasive Candida eruptions by wiping out competing, beneficial bacteria.
Until now, the immune cells that got most of the credit for defending the body against Candida were the small, round lymphocytes of the T cell type, called TH17. These cells were also the ones to take the blame when this defence failed.
In the new study, postdoctoral fellow Dr Jan Dobeš, working together with colleagues in Abramson’s lab, discovered that a powerful commando unit of TH17 cells capable of fighting Candida cannot be generated without crucial early support from an entirely different contingent: a subset of rare lymphoid cells known as type-3 innate lymphoid cells, or ILC3, that express a gene called the autoimmune regulator, or Aire
The two groups of cells belong to the two different arms of the immune system, which, like normal soldiers and specialised ‘commando’ units, join forces against a common enemy. The Aire-ILC3s – part of the more ancient, innate arm – spring into action almost immediately upon encountering a threat – in this case, a Candida infection. The TH17s belong to the immune system’s more recent, adaptive arm, which takes several days or even weeks to respond, but which launches a much more targeted and potent attack than the innate one.
The scientists found that as soon as Candida starts infecting tissues, the Aire-ILC3s engulf the yeast whole, chop them up and display some of the yeast pieces on their surfaces. In this way, the bits are presented to the TH17s, a few of which are generally on call in the lymph nodes, ready for an infection alert. This kind of presentation instructs the specialised T cells to start dividing rapidly, soaring in number from a few lone commandos to several hundred or even thousands of Candida-specific fighters, capable of destroying the yeast at the sites of infection.
“We have identified a previously unrecognised immune system weapon that is indispensable for orchestrating an effective response against the fungal infection,” Abramson said.
Abramson became intrigued by Candida because it commonly leads to severe, chronic infections in people with a rare autoimmune syndrome caused by defects in the Aire gene. Abramson’s lab had conducted extensive studies of this gene, helping to clarify its role in preventing autoimmune disorders. That research, as well as studies by other scientists, had shown that Aire-expressing cells in the thymus instruct developing T cells to refrain from attacking the body’s own tissues. When Aire is defective, T cells fail to receive proper instructions, consequently causing widespread autoimmunity that wreaks havoc in multiple body organs. But one puzzle remained: Why would Aire-deficient patients suffering from a devastating autoimmune syndrome also develop chronic Candida infections?
While trying to complete the Aire puzzle, Dobeš and colleagues found that outside the thymus, Aire is also expressed in a small subset of ILC3s in the lymph nodes. The researchers then genetically engineered two groups of mice: One lacked Aire in the thymus, and the other group lacked it in the ILC3s in the lymph nodes. The first group developed autoimmunity but was able to successfully fight off Candida. In contrast, those in the second group, the ones lacking Aire in ILC3s, were without autoimmunity, but were unable to generate numerous Candida-specific TH17s. Consequently, they failed to effectively eliminate Candida infections. In other words, without Aire-expressing ILC3s, the specialised T cells needed for fighting Candida were not produced in sufficient numbers.
“We found an entirely new role for Aire, one that it plays in the lymph nodes – turning on a mechanism that increases the numbers of Candida-fighting T cells,” Dr Dobeš explained.
These findings open up new directions of research that in the future may help develop new treatments for severe Candida, and possibly for other fungal infections. The newly discovered mechanism might, for example, help produce large numbers of Candida-fighting T cells to be used in cell therapy. If scientists one day decode the signals by which Aire-ILC3s boost T cell proliferation, they might serve as the basis for new therapies.
Source: Weizmann Institute of Science
