The cells that keep fungal infections at bay

Candida albicans. Credit: Wikipedia.

Of all the fungi that live in the human body, the most infamous is probably Candida yeast. This distant cousin of baker’s yeast is known to cause various types of thrush which can be a major nuisance, but it can also lead to an invasive infection which can, on occasion, prove fatal. In a study published today in Natural immunologyA research team from the Weizmann Institute of Science led by Professor Jakub Abramson has discovered a previously unknown defense mechanism used by the immune system to fight Candida infections.

Candida is present in low levels in the body of most healthy people, forming part of the microbiome – a diverse spectrum of microbes that reside peacefully in our gut and on our skin. Under normal circumstances, Candida is controlled by the immune system, but it can occasionally grow excessively, invading the lining of the mouth, vagina, skin or other parts of the body. In severe cases, it can spread to the bloodstream and from there to the kidneys. Such life-threatening infections can occur when a person’s immune system has been weakened, for example, by AIDS or by immunosuppressive drugs such as cancer chemotherapy or steroids. Antibiotics, which eliminate many beneficial bacteria from our microbiome, can also trigger local or invasive Candida outbreaks by giving this yeast an unfair advantage over other microorganisms. This is why, for example, women sometimes develop vaginal yeast infection after taking antibiotics.

Until now, the most recognized immune cells for defending the body against Candida were the small round T-cell type lymphocytes, called TH17. These cells were also the ones blamed when this defense failed.

In the new study, postdoctoral fellow Dr. Jan Dobeš, working with colleagues in Abramson’s lab in Weizmann’s Department of Immunology and Regenerative Biology, found that a powerful commando unit of TH17 cells capable of fighting candidiasis cannot be generated without crucial early support from an entirely different contingent: a subset of rare lymphoid cells called type 3 innate lymphoid cells, or ILC3, which express a gene called autoimmune regulator, or Aire

The two groups of cells belong to the two different arms of the immune system which, like foot patrols and specialized units, join forces against a common enemy. Part of the oldest innate arm, Aire-ILC3 kicks into action almost immediately upon encountering a threat, in this case, a Candida infection. The THThe 17s belong to the newer adaptive arm of the immune system, which takes days or even weeks to react, but which launches a much more targeted and powerful attack than the innate one.

Credit: Weizmann Institute of Science

The scientists found that as soon as Candida starts infecting the tissues, the Aire-ILC3s engulf the whole yeast, chopping them up and displaying some of the yeast pieces on their surfaces. This is how these bits are presented to the TH17, a few of which are usually on guard in the lymph nodes, ready for infection alert. This type of presentation directs specialized T cells to begin dividing rapidly, growing from a few isolated commandos to hundreds or even thousands of Candida-specific fighters capable of destroying yeast at sites of infection.

“We have identified a previously unrecognized immune system weapon that is critical to orchestrating an effective response against fungal infection,” Abramson said.

Abramson was intrigued by Candida because it typically leads to serious chronic infections in people with a rare autoimmune syndrome caused by defects in the Aire gene. Abramson’s lab had conducted extensive studies on this gene, helping to clarify its role in preventing autoimmune diseases. This research, along with 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 faulty, the T cells don’t get the proper instructions, causing widespread autoimmunity that wreaks havoc in multiple organs in the body. But one enigma remained: why would Aire-deficient patients suffering from a devastating autoimmune syndrome also develop chronic Candida infections?

In trying to complete the Aire puzzle, Dobeš and colleagues discovered that apart from the thymus, Aire is also expressed in a small subset of ILC3 in the lymph nodes. The researchers then genetically modified two groups of mice: one lacked Aire in the thymus, and the other group lacked it in the ILC3s of the lymph nodes. The first group developed autoimmunity but managed to fight off Candida. In contrast, those in the second group, those lacking Aire in ILC3s, did not suffer from autoimmunity, but were unable to generate many Candida-specific TH17s. Therefore, they failed to eliminate Candida infections effectively. In other words, without Aire-expressing ILC3s, the specialized T cells needed to fight Candida were not produced in sufficient numbers.

“We found an entirely new role for Aire, the one it plays in the lymph nodes, by activating a mechanism that increases the number of Candida-fighting T cells,” says Dobeš.

These findings open up new directions of research that, in the future, could help develop new treatments for severe Candida, and possibly for other fungal infections. The newly discovered mechanism could, for example, help produce large numbers of Candida-fighting T cells for use in cell therapy. And if scientists ever identify the signals by which Aire-ILC3 stimulate T cell proliferation, these signals themselves could form the basis of new therapies.

Identification of lymph node cells that may play an important role in immune tolerance

More information:
Jan Dobeš et al, Extrathymic expression of Aire controls the induction of an effective TH17 cell-mediated immune response against Candida albicans, Natural immunology (2022). DOI: 10.1038/s41590-022-01247-6

Provided by Weizmann Institute of Science

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