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A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection

In many infectious diseases, the immune response operates as a double-edged sword. While required for protective immunity, infection-induced inflammation can be detrimental if it is not properly controlled, causing collateral body damage and potentially leading to death. It is in this context that t...

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Autores principales: De Trez, Carl, Stijlemans, Benoit, Bockstal, Viki, Cnops, Jennifer, Korf, Hannelie, Van Snick, Jacques, Caljon, Guy, Muraille, Eric, Humphreys, Ian R., Boon, Louis, Van Ginderachter, Jo A., Magez, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325990/
https://www.ncbi.nlm.nih.gov/pubmed/32655552
http://dx.doi.org/10.3389/fimmu.2020.01085
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author De Trez, Carl
Stijlemans, Benoit
Bockstal, Viki
Cnops, Jennifer
Korf, Hannelie
Van Snick, Jacques
Caljon, Guy
Muraille, Eric
Humphreys, Ian R.
Boon, Louis
Van Ginderachter, Jo A.
Magez, Stefan
author_facet De Trez, Carl
Stijlemans, Benoit
Bockstal, Viki
Cnops, Jennifer
Korf, Hannelie
Van Snick, Jacques
Caljon, Guy
Muraille, Eric
Humphreys, Ian R.
Boon, Louis
Van Ginderachter, Jo A.
Magez, Stefan
author_sort De Trez, Carl
collection PubMed
description In many infectious diseases, the immune response operates as a double-edged sword. While required for protective immunity, infection-induced inflammation can be detrimental if it is not properly controlled, causing collateral body damage and potentially leading to death. It is in this context that the potent anti-inflammatory cytokine interleukin-10 (IL-10) is required to dampen the pro-inflammatory immune response that hallmarks trypanosomosis. Effective control of this infection requires not just the action of antibodies specific for the parasite's variable surface glycoprotein (VSG) coat antigens, but also a pro-inflammatory immune response mediated mainly by IFNγ, TNF, and NO. However, strict control of inflammation is mandatory, as IL-10-deficient mice succumb from an unrestrained cytokine storm within 10 days of a Trypanosome brucei infection. The relevant cellular source of IL-10 and the associated molecular mechanisms implicated in its trypanosomosis associated production are poorly understood. Using an IL-10 reporter mouse strain (Vert-X), we demonstrate here that NK cells, CD8(+) T cells and CD4(+) T cells as well as B cells and plasma cells constitute potential cellular sources of IL-10 within the spleen and liver during acute infection. The IL-10 wave follows peak pro-inflammatory cytokine production, which accompanied the control of peak parasitemia. Similar results were observed following conventional experimental needle infection and physiological infections via T. brucei-infected tsetse flies. Our results show that conditional T cell-specific ablation of the IL-10 regulating Prdm1 gene (encoding for the Blimp-1 transcription factor), leads to an uncontrolled trypanosome-induced pro-inflammatory syndrome like the one observed in infected IL-10-deficient mice. This result indicates that the biological role of IL-10-derived from non-T cells, including NK cells, is of minor importance when considering host survival. The cytokine IL-27 that is also considered to be an IL-10 regulator, did not affect IL-10 production during infection. Together, these data suggest that T. brucei activates a Blimp-1-dependent IL-10 regulatory pathway in T cells that acts as a critical anti-inflammatory rheostat, mandatory for host survival during the acute phase of parasitemia.
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spelling pubmed-73259902020-07-09 A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection De Trez, Carl Stijlemans, Benoit Bockstal, Viki Cnops, Jennifer Korf, Hannelie Van Snick, Jacques Caljon, Guy Muraille, Eric Humphreys, Ian R. Boon, Louis Van Ginderachter, Jo A. Magez, Stefan Front Immunol Immunology In many infectious diseases, the immune response operates as a double-edged sword. While required for protective immunity, infection-induced inflammation can be detrimental if it is not properly controlled, causing collateral body damage and potentially leading to death. It is in this context that the potent anti-inflammatory cytokine interleukin-10 (IL-10) is required to dampen the pro-inflammatory immune response that hallmarks trypanosomosis. Effective control of this infection requires not just the action of antibodies specific for the parasite's variable surface glycoprotein (VSG) coat antigens, but also a pro-inflammatory immune response mediated mainly by IFNγ, TNF, and NO. However, strict control of inflammation is mandatory, as IL-10-deficient mice succumb from an unrestrained cytokine storm within 10 days of a Trypanosome brucei infection. The relevant cellular source of IL-10 and the associated molecular mechanisms implicated in its trypanosomosis associated production are poorly understood. Using an IL-10 reporter mouse strain (Vert-X), we demonstrate here that NK cells, CD8(+) T cells and CD4(+) T cells as well as B cells and plasma cells constitute potential cellular sources of IL-10 within the spleen and liver during acute infection. The IL-10 wave follows peak pro-inflammatory cytokine production, which accompanied the control of peak parasitemia. Similar results were observed following conventional experimental needle infection and physiological infections via T. brucei-infected tsetse flies. Our results show that conditional T cell-specific ablation of the IL-10 regulating Prdm1 gene (encoding for the Blimp-1 transcription factor), leads to an uncontrolled trypanosome-induced pro-inflammatory syndrome like the one observed in infected IL-10-deficient mice. This result indicates that the biological role of IL-10-derived from non-T cells, including NK cells, is of minor importance when considering host survival. The cytokine IL-27 that is also considered to be an IL-10 regulator, did not affect IL-10 production during infection. Together, these data suggest that T. brucei activates a Blimp-1-dependent IL-10 regulatory pathway in T cells that acts as a critical anti-inflammatory rheostat, mandatory for host survival during the acute phase of parasitemia. Frontiers Media S.A. 2020-06-04 /pmc/articles/PMC7325990/ /pubmed/32655552 http://dx.doi.org/10.3389/fimmu.2020.01085 Text en Copyright © 2020 De Trez, Stijlemans, Bockstal, Cnops, Korf, Van Snick, Caljon, Muraille, Humphreys, Boon, Van Ginderachter and Magez. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
De Trez, Carl
Stijlemans, Benoit
Bockstal, Viki
Cnops, Jennifer
Korf, Hannelie
Van Snick, Jacques
Caljon, Guy
Muraille, Eric
Humphreys, Ian R.
Boon, Louis
Van Ginderachter, Jo A.
Magez, Stefan
A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection
title A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection
title_full A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection
title_fullStr A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection
title_full_unstemmed A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection
title_short A Critical Blimp-1-Dependent IL-10 Regulatory Pathway in T Cells Protects From a Lethal Pro-inflammatory Cytokine Storm During Acute Experimental Trypanosoma brucei Infection
title_sort critical blimp-1-dependent il-10 regulatory pathway in t cells protects from a lethal pro-inflammatory cytokine storm during acute experimental trypanosoma brucei infection
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325990/
https://www.ncbi.nlm.nih.gov/pubmed/32655552
http://dx.doi.org/10.3389/fimmu.2020.01085
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