title: Vitamin D Antagonises the Suppressive Effect of Inflammatory Cytokines on CTLA-4 Expression and Regulatory Function.
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.
authors.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.
authors.forename: Louisa E
authors.initials: LE
authors.lastname: Jeffery
authors.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.
authors.forename: Omar S
authors.initials: OS
authors.lastname: Qureshi
authors.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.
authors.forename: David
authors.initials: D
authors.lastname: Gardner
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free Campus, University College London, London, United Kingdom.
authors.forename: Tie Z
authors.initials: TZ
authors.lastname: Hou
authors.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.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Briggs
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free Campus, University College London, London, United Kingdom.
authors.forename: Blagoje
authors.initials: B
authors.lastname: Soskic
authors.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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Baker
authors.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; Department of Rheumatology, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom.
authors.forename: Karim
authors.initials: K
authors.lastname: Raza
authors.affiliation: UCL Institute of Immunity and Transplantation, Royal Free Campus, University College London, London, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Sansom
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D016466:CHO Cells; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D002117:Calcitriol / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000378:metabolism*; D004705:Endocytosis; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D058504:Th17 Cells / Q000166:cytology; D014807:Vitamin D / Q000378:metabolism*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; D016207:Cytokines; D018167:Receptors, Calcitriol; D014807:Vitamin D; D002117:Calcitriol