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. 2011 Aug;23(8):519-28.
doi: 10.1093/intimm/dxr045. Epub 2011 Jun 22.

Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling

Danny Bruce  1 , Sanhong Yu, Jot Hui Ooi, Margherita T Cantorna
Affiliations

Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling

Danny Bruce et al. Int Immunol. 2011 Aug.

Abstract

Multiple pathways converge to result in the overexpression of T(h)17 cells in the absence of either vitamin D or the vitamin D receptor (VDR). CD4(+) T cells from VDR knockout (KO) mice have a more activated phenotype than their wild-type (WT) counterparts and readily develop into T(h)17 cells under a variety of in vitro conditions. Vitamin D-deficient CD4(+) T cells also overproduced IL-17 in vitro and 1,25 dihydroxyvitamin D(3) inhibited the development of T(h)17 cells in CD4(+) T-cell cultures. Conversely, the induction of inducible (i) Tregs was lower in VDR KO CD4(+) T cells than WT and the VDR KO iTregs were refractory to IL-6 inhibition. Host-specific effects of the VDR were evident on in vivo development of naive T cells. Development of naive WT CD4(+) T cells in the VDR KO host resulted in the overexpression of IL-17 and more severe experimental inflammatory bowel disease (IBD). The increased expression of T(h)17 cells in the VDR KO mice was associated with a reduction in tolerogenic CD103(+) dendritic cells. The data collectively demonstrate that T(h)17 and iTreg cells are direct and indirect targets of vitamin D. The increased propensity for development of T(h)17 cells in the VDR KO host results in more severe IBD.

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Figures

Fig. 1.
Fig. 1.
Overproduction of IL-17 in VDR KO T cells. CD4 T cells from WT and VDR KO mice were cultured to induce IL-17 production. Treg cultures included TGF-β1 and Th17 cultures contained IL-6 and TGF-β1. (A) Dot plot showing IL-17-positive CD4+ T cells. Data shown are one representative of six experiments. Numbers indicate percentage of IL-17-producing cells. (B) IL-17A secretion in Th17 cultures of WT and VDR KO T cells. Values are the mean of three individual experiments ± SEM. VDR KO cultures contained significantly more IL-17 than WT. (C) mRNA expression of IL-17F, IL-21, IL-22 and IL23R in Th17 cultured CD4+ T cells. Values are the mean of three experiments ± SEM. *VDR KO cells values were significantly higher than WT, P < 0.05. (D) Th17 induction by TGF-β1 plus IL-21 or IL-6 plus IL-1α. Numbers indicate percentage of IFN-γ- or IL-17-secreting cells in the cultures. Data shown are one representative of two experiments.
Fig. 2.
Fig. 2.
Fewer iTreg cells that are refractory to IL-6 inhibition in the absence of the VDR. (A) Expression of FoxP3 in CD4+ T cells cultured in Th0, Th17 and Treg conditions. Values are the mean ± SEM of three independent experiments. (B) Representative dot plots for the data shown in A. (C) IL-10 production by WT and VDR KO CD4+ T cells cultured in Th0, Th17 and Treg conditions. Data shown are the mean ± SEM of three individual experiments. VDR KO values were significantly different than WT in the Th17 cultures. The values between WT Treg and WT Th17 were significantly different for both FoxP3 and IL-10. The values between VDR KO T reg and VDR KO Th17 were significantly different for IL-10.
Fig. 3.
Fig. 3.
Vitamin D or 1,25D3 deficiency induces and 1,25D3 treatment inhibits Th17 cells. Representative dot plots of the CD4+/IL-17-secreting T cells from different in vitro and in vivo 1,25D3 and vitamin D treatments. (A) WT CD4+ T cells were induced to become Treg or Th17 cells in the presence and absence of 25 nM 1,25D3. (B) WT and 1,25D3-deficient CD4+ T cells were induced to become Treg or Th17 cells. (C) Vitamin D sufficient and vitamin D-deficient mice were used as a source of CD4+ T cells for Treg and Th17 cultures, respectively. Data shown are one representative of three experiments. Supplementary Figure S2, available at International Immunology Online, shows the mean ± SEM values.
Fig. 4.
Fig. 4.
VDR KO mice have significantly fewer naive CD4+ T cells. (A) Bar graphs showing the percentages of naive and memory CD4+ T cells in WT and VDR KO mice. Naive cells were either CD44low (CD44lo) or CD25−/CD62L+/CD44low (naive); memory cells were either CD44high (CD44hi) or CD25−/CD62L−/CD44high (memory). Data are presented as mean ± SEM (n = 9 for WT and n = 8 for VDR KO). Representative dot plots from one representative experiment of three showing the percentages of (B) IL-17 and (C) FoxP3+ cells from naive CD4+ T cells cultured in either Th17 or Treg conditions. Numbers indicate percentages of IL-17- or FoxP3-positive cells.
Fig. 5.
Fig. 5.
WT T cells that develop in a VDR KO host induce more rapid IL-17 secretion and weight loss. CD4/CD45RBhigh T cells of donor origin were isolated from VDR KO and WT BM chimeras. The donor-derived CD4/CD45RBhigh T cells were injected into Rag KO recipients. Groups were uninjected control Rag KO (Ctrl), and the following donor → host pairs: WT–WT, VDR KO–WT (KO–WT) and WT–VDR KO (WT–KO). (A) The percent change in BW over time is plotted ± SEM for each group of Rag KO recipients. (B) CD4 T cells were evaluated for IFN-γ production and (C) IL-17 production in either the IEL or the spleen of the Rag KO recipients. Data are mean ± SEM with n = 4 for each group. *P < 0.05 and **P < 0.01.
Fig. 6.
Fig. 6.
VDR expression in non-lymphoid tissues suppresses the development of naive T cells into Th17 cells. WT CD4/CD45RBhigh T cells were transferred to Rag KO and VDR/Rag double (D) KO recipients. (A) The percent change in BW over time is plotted ± SEM for each group, n = 4. The experiment was terminated at 3 week when several of the DKO recipients had lost 20% of their BW. (B) Representative colonic sections of Rag KO (histopathology score of section shown = 3.0) and DKO (histopathology score of section shown = 8.0) recipients sacrificed 3 weeks post-transfer. Scores provided here reflect the score of the sections shown. (C) Histopathology scores for the Rag KO and DKO recipients of naive T cells, n = 4 per group, mean ± SEM. At 3 weeks post-transfer, the composition of the IEL and spleen was evaluated by flow cytometry. (D) CD4+ T cells in the IEL and spleen. (E) CD4/CD62L staining and (F) CD4/CD25 staining of the IEL. (G) The percentage of IL-17 secreting T cells in the IEL and (H) spleen. Values are mean ± SEM and represent two experiments, n = 4 mice per group. Values in the DKO recipient are significantly different than the Rag KO recipient, *P < 0.05.
Fig. 7.
Fig. 7.
Decreased tolerogenic DCs in the absence of the VDR. (A) A representative dot plot of the CD103- and CD11c-positive cells in the MLN of WT and VDR KO mice is shown. Values are the mean CD103+/CD11c+ cell frequencies of four mice per group ± SEM. (B) The frequency of CD103+CD11c+ DCs in the MLN and IEL of Rag KO and DKO mice. Values are mean ± SEM and represent two experiments, n = 4 mice per group.
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References

    1. Podolsky DK. Inflammatory bowel disease. N. Engl. J. Med. 2002;347:417. - PubMed
    1. Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 2006;116:1310. - PMC - PubMed
    1. Poussier P, Ning T, Banerjee D, Julius M. A unique subset of self-specific intraintestinal T cells maintains gut integrity. J. Exp. Med. 2002;195:1491. - PMC - PubMed
    1. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat. Rev. Immunol. 2008;8:523. - PMC - PubMed
    1. Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J. Exp. Med. 2007;204:1757. - PMC - PubMed

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