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Vitamin D Antagonises the Suppressive Effect of Inflammatory Cytokines on CTLA-4 Expression and Regulatory Function.

Jeffery LE, Qureshi OS, Gardner D, Hou TZ, Briggs Z, Soskic B, Baker J, Raza K, Sansom DM - PLoS ONE (2015)

Bottom Line: Th17 cells are emerging as significant players in autoimmunity as well as other diseases.Furthermore, its transendocytic function was maintained such that T cells generated in the presence of Th17 conditions and 1,25(OH)2D3 were highly effective at capturing CTLA-4 ligands from antigen presenting cells and suppressing T cell division.Taken together, these data reveal an inhibitory effect of Th17 polarising conditions upon CTLA-4-mediated regulation and show that 1,25(OH)2D3 counteracts this effect.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom.

ABSTRACT
The immune suppressive protein CTLA-4 is constitutively expressed by Tregs and induced in effector T cells upon activation. Its crucial role in adaptive immunity is apparent from the fatal autoimmune pathology seen in CTLA-4 knockout mice. However, little is known regarding factors that regulate CTLA-4 expression and their effect upon its function to remove CD80 and CD86 from antigen presenting cells by transendocytosis. Th17 cells are emerging as significant players in autoimmunity as well as other diseases. Therefore, in this study we have examined the effects of Th17 polarising conditions on CTLA-4 expression and function in human T cells and show that Th17 conditions can suppress the expression of CTLA-4 and its transendocytic function. In contrast to Th17 cells, vitamin D is inversely associated with autoimmune disease. We have previously shown a striking ability of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) to enhance CTLA-4, however, its effects upon B7 transendocytosis and its activity in the context of inflammation remained unknown. Here we show that induction of CTLA-4 by 1,25(OH)2D3 can actually be enhanced in the presence of Th17 polarising cytokines. Furthermore, its transendocytic function was maintained such that T cells generated in the presence of Th17 conditions and 1,25(OH)2D3 were highly effective at capturing CTLA-4 ligands from antigen presenting cells and suppressing T cell division. Taken together, these data reveal an inhibitory effect of Th17 polarising conditions upon CTLA-4-mediated regulation and show that 1,25(OH)2D3 counteracts this effect. Given the importance of CTLA-4-mediated suppression in the control of autoimmune diseases, our novel data highlight the importance of vitamin D in inflammatory settings.

No MeSH data available.


Related in: MedlinePlus

Vitamin D receptor (VDR) expression is increased by TGFβ in the presence of Th17 polarising cytokines.CD4+CD25- T cells were stimulated with antiCD3CD28 antibodies for 18 hours in the presence of recombinant cytokines and 1,25(OH)2D3 as shown and VDR mRNA measured by qPCR. Expression was normalized to 18S RNA and is plotted relative to expression in the absence of recombinant cytokines or 1,25(OH)2D3. Data are from four donors. Bars show median values and error bars indicate semi interquartile range.
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pone.0131539.g004: Vitamin D receptor (VDR) expression is increased by TGFβ in the presence of Th17 polarising cytokines.CD4+CD25- T cells were stimulated with antiCD3CD28 antibodies for 18 hours in the presence of recombinant cytokines and 1,25(OH)2D3 as shown and VDR mRNA measured by qPCR. Expression was normalized to 18S RNA and is plotted relative to expression in the absence of recombinant cytokines or 1,25(OH)2D3. Data are from four donors. Bars show median values and error bars indicate semi interquartile range.

Mentions: Since 1,25(OH)2D3 exerts its effects through the steroidal nuclear vitamin D receptor (VDR), we investigated the impact of the above treatments on VDR expression. As shown in Fig 4, TGFβ increased VDR mRNA relative to control. This effect was maintained under Th17 conditions but inflammatory cytokines, IL-1β, IL-6 and IL-23, did not enhance VDR without TGFβ. Together these data support the hypothesis that increased VDR expression, seen under Th17 conditions, is the result of the influence of TGFβ. Moreover this suggests that the enhanced effect of 1,25(OH)2D3 on CTLA-4 expression under Th17 conditions, compared with Th0 conditions, may involve increased VDR expression.


Vitamin D Antagonises the Suppressive Effect of Inflammatory Cytokines on CTLA-4 Expression and Regulatory Function.

Jeffery LE, Qureshi OS, Gardner D, Hou TZ, Briggs Z, Soskic B, Baker J, Raza K, Sansom DM - PLoS ONE (2015)

Vitamin D receptor (VDR) expression is increased by TGFβ in the presence of Th17 polarising cytokines.CD4+CD25- T cells were stimulated with antiCD3CD28 antibodies for 18 hours in the presence of recombinant cytokines and 1,25(OH)2D3 as shown and VDR mRNA measured by qPCR. Expression was normalized to 18S RNA and is plotted relative to expression in the absence of recombinant cytokines or 1,25(OH)2D3. Data are from four donors. Bars show median values and error bars indicate semi interquartile range.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4489761&req=5

pone.0131539.g004: Vitamin D receptor (VDR) expression is increased by TGFβ in the presence of Th17 polarising cytokines.CD4+CD25- T cells were stimulated with antiCD3CD28 antibodies for 18 hours in the presence of recombinant cytokines and 1,25(OH)2D3 as shown and VDR mRNA measured by qPCR. Expression was normalized to 18S RNA and is plotted relative to expression in the absence of recombinant cytokines or 1,25(OH)2D3. Data are from four donors. Bars show median values and error bars indicate semi interquartile range.
Mentions: Since 1,25(OH)2D3 exerts its effects through the steroidal nuclear vitamin D receptor (VDR), we investigated the impact of the above treatments on VDR expression. As shown in Fig 4, TGFβ increased VDR mRNA relative to control. This effect was maintained under Th17 conditions but inflammatory cytokines, IL-1β, IL-6 and IL-23, did not enhance VDR without TGFβ. Together these data support the hypothesis that increased VDR expression, seen under Th17 conditions, is the result of the influence of TGFβ. Moreover this suggests that the enhanced effect of 1,25(OH)2D3 on CTLA-4 expression under Th17 conditions, compared with Th0 conditions, may involve increased VDR expression.

Bottom Line: Th17 cells are emerging as significant players in autoimmunity as well as other diseases.Furthermore, its transendocytic function was maintained such that T cells generated in the presence of Th17 conditions and 1,25(OH)2D3 were highly effective at capturing CTLA-4 ligands from antigen presenting cells and suppressing T cell division.Taken together, these data reveal an inhibitory effect of Th17 polarising conditions upon CTLA-4-mediated regulation and show that 1,25(OH)2D3 counteracts this effect.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom.

ABSTRACT
The immune suppressive protein CTLA-4 is constitutively expressed by Tregs and induced in effector T cells upon activation. Its crucial role in adaptive immunity is apparent from the fatal autoimmune pathology seen in CTLA-4 knockout mice. However, little is known regarding factors that regulate CTLA-4 expression and their effect upon its function to remove CD80 and CD86 from antigen presenting cells by transendocytosis. Th17 cells are emerging as significant players in autoimmunity as well as other diseases. Therefore, in this study we have examined the effects of Th17 polarising conditions on CTLA-4 expression and function in human T cells and show that Th17 conditions can suppress the expression of CTLA-4 and its transendocytic function. In contrast to Th17 cells, vitamin D is inversely associated with autoimmune disease. We have previously shown a striking ability of 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) to enhance CTLA-4, however, its effects upon B7 transendocytosis and its activity in the context of inflammation remained unknown. Here we show that induction of CTLA-4 by 1,25(OH)2D3 can actually be enhanced in the presence of Th17 polarising cytokines. Furthermore, its transendocytic function was maintained such that T cells generated in the presence of Th17 conditions and 1,25(OH)2D3 were highly effective at capturing CTLA-4 ligands from antigen presenting cells and suppressing T cell division. Taken together, these data reveal an inhibitory effect of Th17 polarising conditions upon CTLA-4-mediated regulation and show that 1,25(OH)2D3 counteracts this effect. Given the importance of CTLA-4-mediated suppression in the control of autoimmune diseases, our novel data highlight the importance of vitamin D in inflammatory settings.

No MeSH data available.


Related in: MedlinePlus