Vitamin D-binding protein controls T cell responses to vitamin D

BMC Immunology

Carsten Geisler¹  Charlotte Menné Bonefeld¹  Niels Ødum¹  Anders Woetmann¹  Peter Schjerling²  Trine Bøegh Levring¹  Marina Rode von Essen¹  Martin Kongsbak¹ 

[1]Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

[2]Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

关键词: Cubilin;    Megalin;    CYP27B1;    Vitamin D-binding protein;    Vitamin D;    T cell activation;    T cells;   

Others  :  1077704
DOI  :  10.1186/s12865-014-0035-2

 received in 2014-04-04, accepted in 2014-08-29,  发布年份 2014

【 摘 要 】

Background

In vitro studies have shown that the active form of vitamin D₃, 1α,25-dihydroxyvitamin D3 (1,25(OH)₂D₃), can regulate differentiation of CD4⁺ T cells by inhibiting Th1 and Th17 cell differentiation and promoting Th2 and Treg cell differentiation. However, the serum concentration of 1,25(OH)₂D₃ is far below the effective concentration of 1,25(OH)₂D₃ found in in vitro studies, and it has been suggested that 1,25(OH)₂D₃ must be produced locally from the inactive precursor 25-hydroxyvitamin D3 (25(OH)D₃) to affect ongoing immune responses in vivo. Although it has been reported that activated T cells express the 25(OH)D-1α-hydroxylase CYP27B1 that converts 25(OH)D₃ to 1,25(OH)₂D₃, it is still controversial whether activated T cells have the capacity to produce sufficient amounts of 1,25(OH)₂D₃ to affect vitamin D-responsive genes. Furthermore, it is not known how the vitamin D-binding protein (DBP) found in high concentrations in serum affects T cell responses to 25(OH)D₃.

Results

We found that activated T cells express CYP27B1 and have the capacity to produce sufficient 1,25(OH)₂D₃ to affect vitamin D-responsive genes when cultured with physiological concentrations of 25(OH)D₃ in serum-free medium. However, if the medium was supplemented with serum or purified DBP, DBP strictly inhibited the production of 1,25(OH)₂D₃ and 25(OH)D₃-induced T cell responses. In contrast, DBP did not inhibit the effect of exogenous 1,25(OH)₂D₃. Actin, arachidonic acid and albumin did not affect the sequestration of 25(OH)D₃ by DBP, whereas carbonylation of DBP did.

Conclusions

Activated T cells express CYP27B1 and can convert 25(OH)D₃ to 1,25(OH)₂D₃ in sufficiently high concentrations to affect vitamin D-responsive genes when cultured in serum-free medium. However, DBP sequesters 25(OH)D₃ and inhibits the production of 1,25(OH)₂D₃ in T cells. To fully exploit the immune-regulatory potential of vitamin D, future studies of the mechanisms that enable the immune system to exploit 25(OH)D₃ and convert it to 1,25(OH)₂D₃in vivo are required.

【 授权许可】

   
2014 Kongsbak et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Murphy KM, Reiner SL: The lineage decisions of helper T cells. Nat Rev Immunol 2002, 2:933-944.
• [2]Zhu J, Yamane H, Paul WE: Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 2010, 28:445-489.
• [3]Littman DR, Rudensky AY: Th17 and regulatory T cells in mediating and restraining inflammation. Cell 2010, 140:845-858.
• [4]Mora JR, Iwata M, von Andrian UH: Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008, 8:685-698.
• [5]Rigby WF, Yirinec B, Oldershaw RL, Fanger MW: Comparison of the effects of 1,25-dihydroxyvitamin D3 on T lymphocyte subpopulations. Eur J Immunol 1987, 17:563-566.
• [6]Reichel H, Koeffler HP, Tobler A, Norman AW: 1 alpha,25-Dihydroxyvitamin D3 inhibits gamma-interferon synthesis by normal human peripheral blood lymphocytes. Proc Natl Acad Sci U S A 1987, 84:3385-3389.
• [7]Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, Walker LS, Lammas DA, Raza K, Sansom DM: 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 2009, 183:5458-5467.
• [8]Thien R, Baier K, Pietschmann P, Peterlik M, Willheim M: Interactions of 1 alpha,25-dihydroxyvitamin D3 with IL-12 and IL-4 on cytokine expression of human T lymphocytes. J Allergy Clin Immunol 2005, 116:683-689.
• [9]van Etten E, Mathieu C: Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. J Steroid Biochem Mol Biol 2005, 97:93-101.
• [10]Palmer MT, Lee YK, Maynard CL, Oliver JR, Bikle DD, Jetten AM, Weaver CT: Lineage-specific effects of 1,25-dihydroxyvitamin D(3) on the development of effector CD4 T cells. J Biol Chem 2011, 286:997-1004.
• [11]Joshi S, Pantalena LC, Liu XK, Gaffen SL, Liu H, Rohowsky-Kochan C, Ichiyama K, Yoshimura A, Steinman L, Christakos S, Youssef S: 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol 2011, 31:3653-3669.
• [12]Urry Z, Chambers ES, Xystrakis E, Dimeloe S, Richards DF, Gabrysova L, Christensen J, Gupta A, Saglani S, Bush A, O’Garra A, Brown Z, Hawrylowicz CM: The role of 1alpha,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells. Eur J Immunol 2012, 42:2697-2708.
• [13]Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM: Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001, 358:1500-1503.
• [14]Amital H, Szekanecz Z, Szucs G, Danko K, Nagy E, Csepany T, Kiss E, Rovensky J, Tuchynova A, Kozakova D, Doria A, Corocher N, Agmon-Levin N, Barak V, Orbach H, Zandman-Goddard G, Shoenfeld Y: Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D? Ann Rheum Dis 2010, 69:1155-1157.
• [15]Ascherio A, Munger KL, Simon KC: Vitamin D and multiple sclerosis. Lancet Neurol 2010, 9:599-612.
• [16]Pierrot-Deseilligny C, Souberbielle JC: Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis. Ther Adv Neurol Disord 2013, 6:81-116.
• [17]Feldman D, Pike JW, Glowacki J: Vitamin D. Elsevier Academic Press, Burlington; 2011.
• [18]Joseph RW, Bayraktar UD, Kim TK, St John LS, Popat U, Khalili J, Molldrem JJ, Wieder ED, Komanduri KV: Vitamin D receptor upregulation in alloreactive human T cells. Hum Immunol 2012, 73:693-698.
• [19]Lemire JM, Ince A, Takashima M: 1,25-Dihydroxyvitamin D3 attenuates the expression of experimental murine lupus of MRL/l mice. Autoimmunity 1992, 12:143-148.
• [20]Jeffery LE, Wood AM, Qureshi OS, Hou TZ, Gardner D, Briggs Z, Kaur S, Raza K, Sansom DM: Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses. J Immunol 2012, 189:5155-5164.
• [21]Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, Butcher EC: DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007, 8:285-293.
• [22]Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, Kamen DL, Wagner M, Bals R, Steinmeyer A, Zugel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL: Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006, 311:1770-1773.
• [23]Adams JS, Ren S, Liu PT, Chun RF, Lagishetty V, Gombart AF, Borregaard N, Modlin RL, Hewison M: Vitamin D-directed rheostatic regulation of monocyte antibacterial responses. J Immunol 2009, 182:4289-4295.
• [24]Jacobs TP, Bilezikian JP: Clinical review: rare causes of hypercalcemia. J Clin Endocrinol Metab 2005, 90:6316-6322.
• [25]von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C: Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol 2010, 11:344-349.
• [26]Kongsbak M, Levring TB, Geisler C, von Essen MR: The vitamin D receptor and T cell function. Front Immunol 2013, 4:1-10.
• [27]Kongsbak M, von Essen MR, Boding L, Levring TB, Schjerling P, Lauritsen JP, Woetmann A, Odum N, Bonefeld CM, Geisler C: Vitamin D up-regulates the vitamin D receptor by protecting it from proteasomal degradation in human CD4+ T cells. PLoS One 2014, 9:e96695.
• [28]Correale J, Ysrraelit MC, Gaitan MI: Immunomodulatory effects of vitamin D in multiple sclerosis. Brain 2009, 132:1146-1160.
• [29]Baeke F, Korf H, Overbergh L, van EE, Verstuyf A, Gysemans C, Mathieu C: Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D(3) in the immune system. J Steroid Biochem Mol Biol 2010, 121:221-227.
• [30]Bikle DD, Siiteri PK, Ryzen E, Haddad JG: Serum protein binding of 1,25-dihydroxyvitamin D: a reevaluation by direct measurement of free metabolite levels. J Clin Endocrinol Metab 1985, 61:969-975.
• [31]Bikle DD, Gee E, Halloran B, Kowalski MA, Ryzen E, Haddad JG: Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J Clin Endocrinol Metab 1986, 63:954-959.
• [32]Safadi FF, Thornton P, Magiera H, Hollis BW, Gentile M, Haddad JG, Liebhaber SA, Cooke NE: Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J Clin Invest 1999, 103:239-251.
• [33]Chun RF, Lauridsen AL, Suon L, Zella LA, Pike JW, Modlin RL, Martineau AR, Wilkinson RJ, Adams J, Hewison M: Vitamin D-binding protein directs monocyte responses to 25-hydroxy- and 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab 2010, 95:3368-3376.
• [34]Bikle DD, Gee E: Free, and not total, 1,25-dihydroxyvitamin D regulates 25-hydroxyvitamin D metabolism by keratinocytes. Endocrinology 1989, 124:649-654.
• [35]Stoeckler JD, Stoeckler HA, Kouttab N, Maizel AL: 1alpha,25-Dihydroxyvitamin D3 modulates CD38 expression on human lymphocytes. J Immunol 1996, 157:4908-4917.
• [36]Pillai S, Bikle DD, Su MJ, Ratnam A, Abe J: 1,25-Dihydroxyvitamin D3 upregulates the phosphatidylinositol signaling pathway in human keratinocytes by increasing phospholipase C levels. J Clin Invest 1995, 96:602-609.
• [37]Matheu V, Back O, Mondoc E, Issazadeh-Navikas S: Dual effects of vitamin D-induced alteration of TH1/TH2 cytokine expression: enhancing IgE production and decreasing airway eosinophilia in murine allergic airway disease. J Allergy Clin Immunol 2003, 112:585-592.
• [38]Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, Verroust PJ, Aminoff M, de la Chapelle A, Moestrup SK, Ray R, Gliemann J, Willnow TE, Christensen EI: Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc Natl Acad Sci U S A 2001, 98:13895-13900.
• [39]Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE: An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 1999, 96:507-515.
• [40]Rowling MJ, Kemmis CM, Taffany DA, Welsh J: Megalin-mediated endocytosis of vitamin D binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells. J Nutr 2006, 136:2754-2759.
• [41]Machii T, Kimura H, Ueda E, Chujo T, Morita T, Katagiri S, Tagawa S, Kitani T: Distribution of Gc protein (vitamin D binding protein) on the surfaces of normal human lymphocytes and leukemic lymphocytes. Acta Haematol 1986, 75:26-29.
• [42]Kerr MC, Teasdale RD: Defining macropinocytosis. Traffic 2009, 10:364-371.
• [43]Koivusalo M, Welch C, Hayashi H, Scott CC, Kim M, Alexander T, Touret N, Hahn KM, Grinstein S: Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling. J Cell Biol 2010, 188:547-563.
• [44]Menné C, Sorensen T, Siersma V, von Essen M, Odum N, Geisler C: Endo- and exocytic rate constants for spontaneous and protein kinase C-activated T cell receptor cycling. Eur J Immunol 2002, 32:616-626.
• [45]Dietrich J, Menne C, Lauritsen JP, von Essen M, Rasmussen AB, Odum N, Geisler C: Ligand-induced TCR down-regulation is not dependent on constitutive TCR cycling. J Immunol 2002, 168:5434-5440.
• [46]Van Baelen H, Bouillon R, De Moor P: Vitamin D-binding protein (Gc-globulin) binds actin. J Biol Chem 1980, 255:2270-2272.
• [47]Otterbein LR, Cosio C, Graceffa P, Dominguez R: Crystal structures of the vitamin D-binding protein and its complex with actin: structural basis of the actin-scavenger system. Proc Natl Acad Sci U S A 2002, 99:8003-8008.
• [48]Bouillon R, Xiang DZ, Convents R, Van Baelen H: Polyunsaturated fatty acids decrease the apparent affinity of vitamin D metabolites for human vitamin D-binding protein. J Steroid Biochem Mol Biol 1992, 42:855-861.
• [49]Calvo M, Ena JM: Relations between vitamin D and fatty acid binding properties of vitamin D-binding protein. Biochem Biophys Res Commun 1989, 163:14-17.
• [50]Chun RF, Peercy BE, Adams JS, Hewison M: Vitamin D binding protein and monocyte response to 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D: analysis by mathematical modeling. PLoS One 2012, 7:e30773.
• [51]Chun RF, Peercy BE, Orwoll ES, Nielson CM, Adams JS, Hewison M: Vitamin D and DBP: the free hormone hypothesis revisited. J Steroid Biochem Mol Biol 2013, ᅟ:ᅟ. doi: 10.1016/j.jsbmb.2013.09.012
• [52]Stead EA, Warren JV: The protein content of the extracellular fluid in normal subjects after venous congestion and in patients with cardiac failure, anoxemia, and fever. J Clin Invest 1944, 23:283-287.
• [53]Witte CL, Witte MH, Dumont AE, Cole WR, Smith JR: Protein content in lymph and edema fluid in congestive heart failure. Circulation 1969, 40:623-630.
• [54]Nystrom T: Role of oxidative carbonylation in protein quality control and senescence. EMBO J 2005, 24:1311-1317.
• [55]Wen JJ, Garg NJ: Proteome expression and carbonylation changes during Trypanosoma cruzi infection and Chagas disease in rats. Mol Cell Proteomics 2012, 11:M111.
• [56]Soundaravally R, Pukazhvandthen P, Zachariah B, Hamide A: Plasma ferritin and indices of oxidative stress in Helicobacter pylori infection among schoolchildren. J Pediatr Gastroenterol Nutr 2013, 56:519-522.
• [57]Thanan R, Oikawa S, Yongvanit P, Hiraku Y, Ma N, Pinlaor S, Pairojkul C, Wongkham C, Sripa B, Khuntikeo N, Kawanishi S, Murata M: Inflammation-induced protein carbonylation contributes to poor prognosis for cholangiocarcinoma. Free Radic Biol Med 2012, 52:1465-1472.
• [58]Arnaud J, Constans J: Affinity differences for vitamin D metabolites associated with the genetic isoforms of the human serum carrier protein (DBP). Hum Genet 1993, 92:183-188.
• [59]Klug-Micu GM, Stenger S, Sommer A, Liu PT, Krutzik SR, Modlin RL, Fabri M: CD40 ligand and interferon-gamma induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes. Immunology 2013, 139:121-128.
• [60]Fabri M, Stenger S, Shin DM, Yuk JM, Liu PT, Realegeno S, Lee HM, Krutzik SR, Schenk M, Sieling PA, Teles R, Montoya D, Iyer SS, Bruns H, Lewinsohn DM, Hollis BW, Hewison M, Adams JS, Steinmeyer A, Zugel U, Cheng G, Jo EK, Bloom BR, Modlin RL: Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci Transl Med 2011, 3:104ra102.
• [61]Edfeldt K, Liu PT, Chun R, Fabri M, Schenk M, Wheelwright M, Keegan C, Krutzik SR, Adams JS, Hewison M, Modlin RL: T-cell cytokines differentially control human monocyte antimicrobial responses by regulating vitamin D metabolism. Proc Natl Acad Sci U S A 2010, 107:22593-22598.
• [62]Nielsen M, Svejgaard A, Skov S, Dobson P, Bendtzen K, Geisler C, Odum N: IL-2 induces beta2-integrin adhesion via a wortmannin/LY294002-sensitive, rapamycin-resistant pathway. Phosphorylation of a 125-kilodalton protein correlates with induction of adhesion, but not mitogenesis. J Immunol 1996, 157:5350-5358.
• [63]Dietrich J, Geisler C: T cell receptor zeta allows stable expression of receptors containing the CD3γ leucine-based receptor-sorting motif. J Biol Chem 1998, 273:26281-26284.
• [64]von Essen M, Nielsen MW, Bonefeld CM, Boding L, Larsen JM, Leitges M, Baier G, Odum N, Geisler C: Protein kinase C (PKC)α and PKCθ are the major PKC isotypes involved in TCR down-regulation. J Immunol 2006, 176:7502-7510.
• [65]Geisler C, Schøller J, Wahi MA, Rubin B, Weiss A: Association of the human CD3-ζ chain with the αβ-T cell receptor/CD3 complex. J Immunol 1990, 145:1761-1767.
• [66]Geisler C, Rubin B, Caspar-Bauguil S, Champagne E, Vangsted A, Hou X, Gajhede M: Structural mutations of C-domains in members of the immunoglobulin superfamily: consequences for the interactions between the T cell antigen receptor and the ζ2homodimer.J Immunol 1992, 148:3469–3477.