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.
Highlights
During inflammation, immune regulatory cytokines are mandatory to preserve host integrity by controlling pathogeninduced immune responses [1]
Clearance of Parasitemia in T. brucei-Infected Mice Is Followed by the Production of IL-10 in Spleen and Liver In Antat1.1E T. brucei-infected wild-type (WT) C57BL/6 mice, peak parasitemia is reached around day 6 post-infection (p.i.) (Supplementary Figure 1) and blood parasitemia control correlates with the development of a pro-inflammatory response characterized by increased levels of Tumor Necrosis Factor (TNF), IFNγ, and IL-6, which peaks around day 7 and decreases toward 10 p.i. (Figures 1A–C)
These results suggest that IL-10 produced in liver and spleen is crucial in dampening pro-inflammatory cytokines induced during parasitemia
Summary
Immune regulatory cytokines are mandatory to preserve host integrity by controlling pathogeninduced immune responses [1]. Experimental T. brucei infections in mice have shown that clearance of the first parasitemia peak is dependent on an early strong type 1 inflammatory immune response, involving IFNγ, Nitric Oxide (NO) and Tumor Necrosis Factor (TNF) production, which correlates with an early activation of monocytes, the recruitment of splenic neutrophils and the development of anemia [24,25,26,27,28]. Post-parasitemia peak (around day 8–9 p.i.), the cellular source of IL-10 is still similar in the liver, whereas, surprisingly, the main splenic IL-10-producing cells become plasma B cells These results were first obtained in a conventional experimental infection model in which mice were challenged with T. brucei parasites via intraperitoneal needle injection. Using T cell conditional Blimp-1 knockout mice, we demonstrate the importance of this transcription factor in dampening trypanosome-mediated inflammation, mainly via the control of T cell activation and IL-10 production, and host survival
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