Respiratory infection response: a case of mistaken identity

Scientists have identified a previously unknown immune cell that plays a crucial role presenting antigens to other immune cells during respiratory virus infections, and could explain how convalescent plasma helps to boost immune responses in virus-infected patients.

When our body faces an infection, it responds with inflammation and fever. This is a sign that the immune system is doing its job and leads to the activation of many cells, like soldiers in an army. Dendritic cells (DCs) are like the generals of that army, activating and instructing the soldiers to kill infected cells by presenting antigens derived from the ‘invaders’ to cells of the immune system.

There are several types of DCs that perform antigen-presenting functions in the body. Conventional DCs continuously scan the body for dangerous invaders, even when there is no infection. When there is inflammation triggered by infection, another subset of DCs emerges from inflammatory monocytes. Because monocyte-derived DCs are easily prepared in vitro from monocytes isolated from human blood, it was always assumed that these cells were very important antigen-presenting cells. Clinical trials using monocyte-derived DCs in cancer therapy have, however, been disappointing.

An international study, led by Bart Lambrecht, Martin Guilliams, Hamida Hammad and Charlotte Scott from the VIB-UGent Center for Inflammation Research, now reveals that monocyte-derived DCs are in fact poor antigen-presenting cells, and have wrongly been assumed to have these functions due to a case of mistaken identity. Their discovery, which could see a rewrite of the immunology textbooks, has been published in the journal Immunity.

The scientists studied mice with a viral respiratory infection with single-cell technologies; single-cell resolution allowed them to finely separate the monocyte-derived cells from other DCs during their response to the infection. They found that monocyte-derived DCs do exist, but do not present antigens. The reason for the confusion is that a lookalike DC emerges — called inflammatory type 2 conventional DC, or inf-cDC2 — that combines some of the best characteristics of monocytes, macrophages and conventional DCs to induce the best form of immunity.

“This was a big surprise for us,” Lambrecht said. “We’ve all been taught that monocyte-derived cells are excellent antigen-presenting cells, certainly when there’s inflammation. Now we show that it’s actually a new hybrid DC type that’s doing all the work. This really changes what we know about the immune system and is very important knowledge for understanding respiratory viral infections and other inflammatory diseases.”

Guilliams added, “It took a massive team effort, but the strength of single-cell sequencing has finally cracked the complex DC code. Many contradicting findings from the last two decades now make much more sense. This also opens tremendous therapeutic opportunities, since vaccination strategies can now be designed to trigger formation of inf-cDC2s and thus generate a stronger antiviral immune response.”

Scott concluded, “Through the use of single-cell technologies, we have been able to align all the findings from the past few years and identify the distinct cell types involved. Moving forward, it will be very interesting to see under what other inflammatory conditions these inf-cDC2s are generated and how they can potentially be targeted therapeutically.”

The findings also have direct relevance for the current COVID-19 pandemic, caused by another respiratory virus. An emergency treatment that is currently being explored is the use of convalescent plasma, or the blood plasma of recovered patients. Study lead author Cedric Bosteels noted, “One of the unique features of the new DCs is that they express functional Fc receptors for antibodies that are found in the plasma of patients who have recovered from COVID-19.”

This study is the first to show that one of the mechanisms through which convalescent plasma and the virus-specific antibodies in it work via boosting of inf-cDC2. Since boosted DCs induce a much stronger immune response, the study reveals a new target for therapeutic intervention for viral infections and other inflammatory diseases.

Image credit: ©stock.adobe.com/au/Rasi

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