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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

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. and Magez, Stefan 2020. 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. Frontiers in Immunology 11 , 1085. 10.3389/fimmu.2020.01085

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)
Publisher: Frontiers Media
ISSN: 1664-3224
Date of First Compliant Deposit: 22 April 2021
Date of Acceptance: 5 May 2020
Last Modified: 27 Apr 2021 09:30
URI: http://orca.cardiff.ac.uk/id/eprint/140646

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