Deoxynivalenol Has the Capacity to Increase Transcription Factor Expression and Cytokine Production in Porcine T Cells

Abstract

Deoxynivalenol (DON) is a Fusarium mycotoxin that frequently contaminates the feed of farm animals. Pigs with their monogastric digestive system are in particular sensitive to DON-contaminated feed. At high concentrations, DON causes acute toxic effects, whereas lower concentrations lead to more subtle changes in the metabolism. This applies in particular to the immune system, for which immunosuppressive but also immunostimulatory phenomena have been described. Research in human and rodent cell lines indicates that this may be partially explained by a binding of DON to the ribosome and subsequent influences on cell signaling molecules like mitogen-activated protein kinases. However, a detailed understanding of the influence of DON on functional traits of porcine immune cells is still lacking. In this study, we investigated the influence of DON on transcription factor expression and cytokine production within CD4 + , CD8 + , and γδ T cells in vitro. At a DON concentration, that already negatively affects proliferation after Concanavalin A stimulation (0.8 µM) an increase of T-bet expression in CD4 + and CD8 + T cells was observed. This increase in T-bet expression coincided with elevated levels of IFN-γ and TNF-α producing T-cell populations. Increases in T-bet expression and cytokine production were found in proliferating and non-proliferating T cells, although increases were more prominent in proliferating cell subsets. Differently, IL-17A production by CD4 + T cells was not influenced by DON. In addition, frequencies of regulatory T cells and their expression of Foxp3 were not affected. In γδ T cells, GATA-3 expression was slightly reduced by DON, whereas T-bet levels were only slightly modulated and hence IFN-γ, TNF-α, or IL-17A production were not affected. Our results show for the single-cell level that DON has the capacity to modulate the expression of transcription factors and related cytokines. In particular, they suggest that for CD4 + and CD8 + T cells, DON can drive T-cell differentiation into a pro-inflammatory type-1 direction, probably depending on the already prevailing cytokine milieu. This could have beneficial or detrimental effects in ongoing immune responses to infection or vaccination.

Influence of deoxynivalenol-contaminated feed on the immune response of pigs after PRRSV vaccination and infection

“…In vitro work from the authors of this study could show that mitogen-induced proliferation and the expression of the co-stimulatory molecules CD27 and CD28 of porcine T cells is negatively affected by doses ≥ 0.8 μM of DON (Vatzia et al 2019 ). However, a follow-up study revealed that a dose of 0.8 μM of DON is capable to increase T-bet expression and production of IFN-γ and TNF-α in porcine CD4 + and CD8 + T cells (Vatzia et al 2020 ), reminiscent of in vivo observations in this study. However, such effects seem to occur in a small dose-dependent window; in vitro work by Hlavová et al ( 2020 ) showed that porcine CD4 + and γδ T cells have a reduced production of IFN-γ, TNF-α and IL-17 following polyclonal stimulation in the presence of 0.034 µM DON.…”

Effects of Deoxynivalenol and Fumonisins Fed in Combination to Beef Cattle: Immunotoxicity and Gene Expression

“…Total leukocyte and neutrophil percentages indicate a more grossly sustained pro-inflammatory response, with CD4 − CD8 + lymphocytes and the CD4:CD8 ratio responding more sensitively. Decreased proliferation of CD4 − CD8 + , CD4 + CD8- and CD4 + CD8 + porcine T cells with DON exposure at levels greater than 0.4 µM and reduced proliferation of peripheral blood mononuclear cells (PBMCs, primarily lymphocytes of unknown CD4/8 phenotypes) in cattle at DON levels as low as 0.21 µM have been observed [ 13 , 25 ]. While true absorption of DON in steers of this study is unknown, even a conservative estimate of blood volume (425 kg average body weight, 9 kg TMR intake/day [ 24 ]) would conclude that cytotoxic DON levels are reported to perturb PBMCs from this species [ 13 ] would be attainable only with a high absorption and distribution of the parent toxin.…”

Establishment of an In Vitro Co-Culture Model of the Piglet Gut to Study Inflammatory Response and Barrier Integrity

“…As a next step, the gut co-culture model stimulated by ConA was used to study the role of potential immunomodulators on ongoing inflammatory reactions in the intestine. ConA is known as a potent antigen-independent mitogen that functions as an inducer, leading T cells to polyclonal proliferation and cytokine in- duction [30,34]. Various nutritional strategies are implemented to help piglets to cope with the post-weaning period and overcome weaning-related difficulties [35][36][37].…”