Developmental Biology - COVID-19|
New Cell Crucial In Response to Respiratory Infection
A newly discovered cell type could play a crucial role during respiratory viral infections like COVID-19...
The findings of this research have a 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.
"One of the unique features of the new dendritic cells (DCs) is that they express functional Fc receptors for antibodies found in the plasma of patients who have recovered from COVID-19."
Cedric Bosteels PhD, Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium and lead author of the paper.
A study just published in Cell, is the first to show one of the mechanisms through which convalescent plasma and the virus-specific antibodies in it work — via boosting inf-cDC2.
Boosted DCs induce a much stronger immune response, this study reveals a new target for therapeutic intervention for viral infections and other inflammatory diseases.
With a discovery that could rewrite immunology textbooks, an international group of scientists, now play a crucial role in identifying antigens to other immune cells found during viral respiratory infections. This discovery could explain how convalescent plasma helps boost immune responses in virus-infected patients.
Scientists from the VIB-UGent Center for Inflammation Research, have found a new type of antigen presenting immune cell, part of an expanding family of dendritic cells (DCs).
Bart Lambrecht, Martin Guilliams, Hamida Hammad, and Charlotte Scott (all of the VIB-UGent Center for Inflammation Research) also identified antigens to other immune cells they found during respiratory virus infections. These antigens might explain how convalescent plasma helps boost immune responses in other virus-infected patients.
Inflammation and Immunity
When our body faces an infection, it responds with inflammation and fever. This is a sign that our immune system is working. This response activates many cells, behaving like soldiers in an immune army. Dendritic cells (DCs) are the generals in that army. They can precisely activate and instruct "soldier cells" to kill infected cells by presenting antigens created from viral "invaders" via our immune system.
There are several types of DCs that perform antigen-presenting functions in the body. A first type of conventional DCs continuously scan the body for dangerous invaders, even without infection. Infection triggers another subset of DCs to emerge from inflammatory monocytes. Because monocyte derived DCs are easily prepared in vitro from monocytes isolated from human blood, it was assumed they were very important antigen-presenting cells. Clinical trials using monocyte-derived DCs in cancer therapy, have been disappointing.
The study reveals that monocyte-derived DCs are poor antigen-presenting cells, but only due to a case of mistaken identity.
The scientists studied mice given a viral respiratory infection (mouse pneumonia and influenza viruses). Single-cell resolution then allowed them to separate monocyte-derived cells from other DCs responding to the infections. They found monocyte-derived DCs do exist, but actually do not make antigens. The reason for all the past confusion are look-alike DCs. These new DCs are now called inflammatory type 2 conventional DCs, or inf-cDC2. They appear to combine some of the best characteristics of monocytes, macrophages, and conventional DCs, and induce the best form of immunity.
"This was a big surprise for us. 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."
Bart Lambrecht PhD, Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
"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."
Martin Guilliams PhD, Laboratory of Immunoregulation and Mucosal Immunology; VIB-UGent Center for Inflammation Research, Ghent, Belgium.
"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."
Charlotte Scott PhD, Laboratory of Immunoregulation and Mucosal Immunology; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting
cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. InfcDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte derived cells, their existence could explain why APC functions have been attributed to MCs.
Cedric Bosteels, Katrijn Neyt,
Manon Vanheerswynghels, Mary J. van Helden, Dorine Sichien, Nincy Debeuf, Sofie De Prijck, Victor Bosteels, Niels Vandamme, Liesbet Martens, Yvan Saeys, Els Louagie, Manon Lesage, David L. Williams, Shiau-Choot Tang, Johannes U. Mayer, Franca Ronchese, Charlotte L. Scott,
Hamida Hammad, Martin Guilliams,
Bart N. Lambrecht.
This study was funded by the European Research Council, University Ghent, Research Foundation Flanders (FWO), and the Health Research Council New Zealand.
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May 11 2020 Fetal Timeline Maternal Timeline News
Macrophages in tissue modules are like isolated villages, whether in lung or liver.
Macrophage act like the village BAKERY (left) or PIZZERIA (right) through complex interactions.
Electricity (BLUE) to run; 2
Orders (PURPLE) from the tissue-specific signals induce
Transcription Factors (RED) to control their 4
Cooking/intracellular machinery (orange) to 5
Process ingredients (input, GREEN) into the 6
End-Product (output BROWN).
CREDIT Natan Shaked/AFTAU.