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. 2017 Nov 6;7(1):14516.
doi: 10.1038/s41598-017-15099-w.

Butyrate and propionate inhibit antigen-specific CD8+ T cell activation by suppressing IL-12 production by antigen-presenting cells

Claudia Nastasi  1 , Simon Fredholm  1 , Andreas Willerslev-Olsen  1 , Morten Hansen  2 , Charlotte Menné Bonefeld  1 , Carsten Geisler  1 , Mads Hald Andersen  1   2 , Niels Ødum  1 , Anders Woetmann  3
Affiliations

Butyrate and propionate inhibit antigen-specific CD8VSports在线直播 - + T cell activation by suppressing IL-12 production by antigen-presenting cells

Claudia Nastasi et al. Sci Rep. .

Abstract

Short chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are products of microbial macronutrients fermentation that distribute systemically and are believed to modulate host immune responses VSports手机版. Recent data have indicated that certain SCFAs, such as butyrate and propionate, directly modulate human dendritic cell (DC) function. Given the role of DCs in initiating and shaping the adaptive immune response, we now explore how SCFAs affect the activation of antigen-specific CD8+ T cells stimulated with autologous, MART1 peptide-pulsed DC. We show that butyrate reduces the frequency of peptide-specific CD8+ T cells and, together with propionate, inhibit the activity of those cells. On the contrary, acetate does not affect them. Importantly, butyrate and propionate inhibit the production of IL-12 and IL-23 in the DCs and exogenous IL-12 fully restores the activation of the MART-1-specific CD8+ T cells, whereas IL-23 has no effect. In conclusion, these results point to a pivotal role of butyrate and propionate in modulating CD8+ T cell activation via the inhibition of IL-12 secretion from DCs. These findings reveal a novel mechanism whereby bacterial fermentation products may modulate CD8+ T cell function with possible implications in anti-cancer immunotherapy. .

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Butyrate and propionate inhibit activation of antigen-specific CTLs. (a) Chart represents the percentages of activated IFN-γ+ TNF-α− and (b) IFN-γ+ TNF-α+- and (c) IFN-γ− TNF-α+-producing CD8+ T cells after 10 days of co-culture with MART-1 pulsed iDCs, mDCs, mDC_A, mDC_B, and mDC_P. Values have been normalized to those CD8+ T cells in co-culture with untreated mDCs that has defined the activation threshold for each individual donor (n = 12). Shown are the percentages of (d) MART-1-specific CD8+ T cells and (e) KI67+ CD8+ T cells in co-cultured with DCs treated as previously mentioned (n = 4). Wilcoxon matched-pairs signed rank tests were run for the a–c analysis, and Mann-Whitney tests for d–e. **P ≤ 0.01, ***P ≤ 0.001.
Figure 2
Figure 2
Butyrate and propionate impairs up-regulation of co-stimulatory molecules on DCs. Charts represent the mean fluorescence intensity (MFI) values of each donor’s sample. Shown are the averages ± standard deviations (SD) (a,b,f n = 14; e n = 12; c,b n = 8); Two-tailed paired Student’s t-tests, *P < 0.05, **P ≤ 0.01, ***P ≤ 0.001.
Figure 3
Figure 3
SCFAs reduce the secretion of IL-6, IL-12, and IL-23 from DCs. Shown are the averages ± standard deviations (SD) of (a) IL-6, (b) IL-12p40, (c) and IL-23 cytokines released into the media by monocyte-derived DCs and detected by ELISA from n = 12 donors. Two-tailed paired Student’s t-tests, *P < 0.05, **P ≤ 0.01, ***P ≤ 0.001.
Figure 4
Figure 4
Gating strategy used for flow cytometry analysis. FACS plots are shown as representative example of the gating strategy used in each experiment, combined with the plots showing the comparison of IFN-γ and TNF-α cytokine production by CD8+ T cells after supplementing the media with eiter IL-12 or IL-23.
Figure 5
Figure 5
Addition of exogenous IL-12 rescues the activity of CTLs in co-cultures with SCFA-treated DCs. Charts represent the percentages of activated IFN-γ+ TNF-α−, IFN-γ+ TNF-α+, and IFN-γ− TNF-α+-producing CD8+ T cells after 10 days of co-culture with MART-1 pulsed iDCs, mDCs, mDC_A, mDC_B, and mDC_P with and without (a–c) IL-12 (donors n = 5), (d–f) IL-23 (n = 3) supplementation into the media. Values have been normalized to those CD8+ T cells in co-culture with untreated mDC that has defined the activation threshold for each individual donor. Multiple t-tests with Holm-Sidak as correction method, *P < 0.05.
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