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

• Published in: PloS one Vol. 10; no. 7; p. e0131539
• Main Authors: Jeffery, Louisa E, Qureshi, Omar S, Gardner, David, Hou, Tie Z, Briggs, Zoe, Soskic, Blagoje, Baker, Jennifer, Raza, Karim, Sansom, David M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.07.2015; Public Library of Science (PLoS)
• Subjects: Adaptive immunity; Animals; Antigen-presenting cells; Antigen-Presenting Cells - cytology; Autoimmune diseases; Autoimmunity; B7 antigen; B7-1 Antigen - metabolism; B7-2 Antigen - metabolism; Biomedical research; Calcitriol; Calcitriol - metabolism; CD80 antigen; CD86 antigen; Cell activation; Cell division; CHO Cells; College campuses; Councils; Cricetinae; Cricetulus; CTLA-4 Antigen - genetics; CTLA-4 Antigen - metabolism; CTLA-4 protein; Cytokines; Cytokines - metabolism; Dendritic cells; Diabetes; Dietary supplements; Effector cells; Endocytosis; Gene Expression Regulation; Genomes; Helper cells; Humans; Immunity; Infections; Inflammation; Inflammation - metabolism; Leukocytes, Mononuclear - metabolism; Ligands; Lupus; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Medical research; Medical schools; Real-Time Polymerase Chain Reaction; Receptors, Calcitriol - metabolism; Rodents; Systematic review; T cells; T-Lymphocytes, Regulatory - cytology; Th17 Cells - cytology; Vitamin D; Vitamin D - metabolism; Vitamin D3
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0131539

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.